Pde10 inhibitors and related compositions and methods

ABSTRACT

Compounds that inhibit PDE10 are disclosed that have utility in the treatment of a variety of conditions, including (but not limited to) psychotic, anxiety, movement disorders and/or neurological disorders such as Parkinson&#39;s disease, Huntington&#39;s disease, Alzheimer&#39;s disease, encephalitis, phobias, epilepsy, aphasia, Bell&#39;s palsy, cerebral palsy, sleep disorders, pain, Tourette&#39;s syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders. Pharmaceutically acceptable salts, stereoisomers, solvates and prodrugs of the compounds are also provided. Also disclosed are compositions containing a compound in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for inhibiting PDE10 in a warm-blooded animal in need of the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/601,100, filed Jan. 20, 2015, which is a divisional application ofU.S. patent application Ser. No. 14/177,952, filed Feb. 11, 2014 (nowU.S. Pat. No. 9,102,643), which is a continuation application of U.S.patent application Ser. No. 13/679,818, filed Nov. 16, 2012 (now U.S.Pat. No. 8,685,975), which is a continuation of U.S. patent applicationSer. No. 13/045,162, filed Mar. 10, 2011 (now U.S. Pat. No. 8,343,970),which claims the benefit under 35 U.S.C. §119(e) of U.S. ProvisionalPatent Application No. 61/313,544, filed Mar. 12, 2010, and U.S.Provisional Patent Application No. 61/430,841, filed Jan. 7, 2011, whichapplications are incorporated herein by reference in their entireties.

BACKGROUND

Technical Field

This invention relates generally to compounds having activity as PDE10inhibitors, and to compositions containing the same, as well as tomethods of treating various disorders by administration of suchcompounds to a warm-blooded animal in need thereof.

Description of the Related Art

Cyclic nucleotide phosphodiesterases (PDEs) are represented by a largesuperfamily of enzymes. PDEs are known to possess a modulararchitecture, with a conserved catalytic domain proximal to the carboxylterminus, and regulatory domains or motifs often near the aminoterminus. The PDE superfamily currently includes more than twentydifferent genes subgrouped into eleven PDE families (Lugnier, C.,“Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target forthe development of specific therapeutic agents.” Pharmacol Ther. 2006March; 109(3):366-98).

A recently described PDE, PDE10, was reported simultaneously by threeindependent groups (Fujishige et al., “Cloning and characterization of anovel human phosphodiesterase that hydrolyzes both cAMP and cGMP(PDE10A),” J Biol Chem 1999, 274:18438-18445; Loughney et al.,“Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclicnucleotide phosphodiesterase,” Gene 1999, 234:109-117; Soderling et al.,“Isolation and characterization of a dual-substrate phosphodiesterasegene family: PDE10A,” Proc Natl Acad Sci USA 1999, 96:7071-7076). PDE10has the capacity to hydrolyze both cAMP and cGMP; however, the K_(m) forcAMP is approximately 0.05 μM, whereas the K_(M) for cGMP is 3 μM. Inaddition, the V_(max) for cAMP hydrolysis is fivefold lower than forcGMP. Because of these kinetics, cGMP hydrolysis by PDE10 is potentlyinhibited by cAMP in vitro, suggesting that PDE10 may function as acAMP-inhibited cGMP phosphodiesterase in vivo. Unlike PDE8 or PDE9,PDE10 is inhibited by IBMX with an IC₅₀ (50% inhibitory concentration)of 2.6 μM. (See Soderling and Beavo, “Regulation of cAMP and cGMPsignaling: new phosphodiesterases and new functions,” Current Opinion inCell Biology, 2000, 12: 174-179.)

PDE10 contains two amino-terminal domains that are similar to thecGMP-binding domains of PDE2, PDE5 and PDE6, which are domains conservedacross a wide variety of proteins. Because of the wide conservation ofthis domain, it is now referred to as the GAF domain (for the GAFproteins: cGMP binding phosphodiesterases; the cynobacterial Anabaenaadenylyl cyclase; and the Escherichia coli transcriptional regulatorfhlA). Although in PDE2, PDE5 and PDE6 the GAF domains bind cGMP, thisis probably not the primary function of this domain in all cases (e.g.,E. coli are not thought to synthesize cGMP). Interestingly, in vitrobinding studies of PDE10 indicate the dissociation constant (K_(d)) forcGMP binding is well above 9 μM. As in vivo concentrations of cGMP arenot thought to reach such high levels in most cells, it seems likelythat either the affinity of PDE10 for cGMP is increased by regulation,or that the primary function of the GAF domain in PDE10 may be forsomething other than cGMP binding.

Inhibitors of the PDE family of enzymes have widely been sought for abroad indication of therapeutic uses. Reported therapeutic uses of PDEinhibitors include allergies, obtrusive lung disease, hypertension,renal carcinoma, angina, congestive heart failure, depression anderectile dysfunction (WO 01/41807 A2). Other inhibitors of PDE have beendisclosed for treatment of ischemic heart conditions (U.S. Pat. No.5,693,652). More specifically, inhibitors of PDE10 have been disclosedfor treatment of certain neurological and psychiatric disordersincluding, Parkinson's disease, Huntington's disease, schizophrenia,delusional disorders, drug-induced psychosis and panic andobsessive-compulsive disorders (U.S. Patent Application No.2003/0032579). PDE10 has been shown to be present at high levels inneurons in areas of the brain that are closely associated with manyneurological and psychiatric disorders. By inhibiting PDE10 activity,levels of cAMP and cGMP are increased within neurons, and the ability ofthese neurons to function properly is thereby improved. Thus, inhibitionof PDE10 is believed to be useful in the treatment of a wide variety ofconditions or disorders that would benefit from increasing levels ofcAMP and cGMP within neurons, including those neurological, psychotic,anxiety and/or movement disorders mentioned above.

While advances have been made with regard to inhibition of PDE10, thereremains a need in the field for inhibitors of PDE10, as well as the needto treat various conditions and/or disorders that would benefit from thesame.

BRIEF SUMMARY

In brief, this invention is generally directed to compounds that haveactivity as PDE10 inhibitors, as well as to methods for theirpreparation and use, and to pharmaceutical compositions containing thesame.

In one embodiment, the compounds have the following general structure(I):

including pharmaceutically acceptable salts, stereoisomers, solvates andprodrugs thereof, wherein A, R₁, R₂ and R₃ are as defined below.

The compounds of this invention have utility over a wide range oftherapeutic applications, and may be used to treat a wide variety ofconditions or disorders that would benefit from increasing levels ofcAMP and cGMP, especially within neurons, including (but not limited to)neurological disorders, such as psychotic disorders, anxiety disorders,movement disorders and/or neurological disorders such as Parkinson'sdisease, Huntington's disease, Alzheimer's disease, encephalitis,phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleepdisorders, pain, Tourette's syndrome, schizophrenia, delusionaldisorders, bipolar disorders, post-traumatic stress disorders,drug-induced psychosis, panic disorders, obsessive-compulsive disorders,attention-deficit disorders, disruptive behavior disorders, autism,depression, dementia, cognitive disorders, epilepsy, insomnias andmultiple sclerosis.

The methods of this invention include administering an effective amountof a compound of the foregoing structures, typically in the form of apharmaceutical composition, to a mammal in need thereof, including ahuman. Thus, in a further embodiment, pharmaceutical compositions aredisclosed containing one or more compounds of the foregoing structuresin combination with a pharmaceutically acceptable carrier or diluent.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates that Compound 1-1 of the present invention(Example 1) administered by intraperitoneal injection significantlyreduces hyperactivity of mice in a psychostimulant (PCP)-induced modelof psychosis as compared to vehicle control.

FIG. 2 illustrates that Compound 1-1 of the present invention(Example 1) administered by oral gavage significantly reduceshyperactivity of mice in a psychostimulant (PCP)-induced model ofpsychosis as compared to vehicle control.

FIG. 3 illustrates that Compound 2-1 of the present invention (Example2) administered by intraperitoneal injection significantly reduceshyperactivity of mice in a psychostimulant (PCP)-induced model ofpsychosis as compared to vehicle control.

FIG. 4 illustrates that Compound 2-1 of the present invention (Example2) administered by oral gavage significantly reduces hyperactivity ofmice in a psychostimulant (PCP)-induced model of psychosis as comparedto vehicle control.

FIG. 5 illustrates that Compound 2-1 of the present invention (Example2) significantly reduces a conditioned avoidance response (CAR) in micetrained in a CAR model of psychosis as compared to vehicle control.

FIG. 6 illustrates that Compound 11-1 of the present invention (Example11) administered by intraperitoneal injection significantly reduceshyperactivity of mice in a psychostimulant (PCP)-induced model ofpsychosis as compared to vehicle control.

FIG. 7 illustrates that Compound 34-1 of the present invention (Example34) significantly reduces a conditioned avoidance response (CAR) in micetrained in a CAR model of psychosis as compared to vehicle control.

FIG. 8 illustrates that Compound 36-1 of the present invention (Example36) significantly reduces a conditioned avoidance response (CAR) in micetrained in a CAR model of psychosis as compared to vehicle control.

FIG. 9 illustrates that Compound 47-1 of the present invention (Example47) significantly reduces a conditioned avoidance response (CAR) in micetrained in a CAR model of psychosis as compared to vehicle control.

FIG. 10 illustrates that Compound 61-1 of the present invention (Example61) significantly reduces a conditioned avoidance response (CAR) in micetrained in a CAR model of psychosis as compared to vehicle control.

FIG. 11 illustrates that Compound 63-1 of the present invention (Example63) significantly reduces a conditioned avoidance response (CAR) in micetrained in a CAR model of psychosis as compared to vehicle control.

FIG. 12 illustrates that Compound 49-1 of the present invention (Example49) significantly reduces a conditioned avoidance response (CAR) in micetrained in a CAR model of psychosis as compared to vehicle control.

FIG. 13 illustrates that Compound 65-10 of the present invention(Example 65, Table 1) significantly reduces a conditioned avoidanceresponse (CAR) in mice trained in a CAR model of psychosis as comparedto vehicle control.

DETAILED DESCRIPTION

As mentioned above, the present invention is directed generally tocompounds useful as PDE10 inhibitors, as well as to methods for theirpreparation and use, and to pharmaceutical compositions containing thesame.

In one embodiment, the PDE10 inhibitors have the following structure(I):

or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrugthereof,

wherein:

-   -   A is:

-   -   R₁ is C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆aralkyl, aryl,        —(CH₂)_(n)O(CH₂)_(m)CH₃ or —(CH₂)_(n)N(CH₃)₂;    -   R₂ is (i) substituted or unsubstituted aryl or (ii) substituted        or unsubstituted heterocyclyl;    -   R₃ is substituted or unsubstituted aryl;    -   R₄ is hydrogen, C₁₋₆alkyl or C₁₋₆haloalkyl;    -   n is 1, 2, 3, 4, 5 or 6; and    -   m is 0, 1, 2, 3, 4, 5 or 6.

As used herein, the above terms have the following meaning:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“C₁₋₆alkyl” means a straight chain or branched, noncyclic or cyclic,unsaturated or saturated aliphatic hydrocarbon radical containing from 1to 6 carbon atoms. Representative saturated straight chain alkylsinclude methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and thelike; while saturated branched alkyls include isopropyl, sec-butyl,isobutyl, tert-butyl, isopentyl, and the like. Representative saturatedcyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and the like; while unsaturated cyclic alkyls include cyclopentenyl andcyclohexenyl, and the like. Unsaturated alkyls contain at least onedouble or triple bond between adjacent carbon atoms (referred to as an“alkenyl” or “alkynyl”, respectively). Representative straight chain andbranched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; whilerepresentative straight chain and branched alkynyls include acetylenyl,propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1-butynyl, and the like.

“C₁₋₆alkylene” or “C₁₋₆alkylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to six carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.

“C₁₋₆alkoxy” refers to a radical of the formula —OR_(a) where R_(a) isan alkyl radical as defined above, for example, methoxy, ethoxy and thelike.

“Aryl” means a hydrocarbon ring system radical comprising hydrogen, 6 to18 carbon atoms and at least one aromatic ring. The aryl radical may bea monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. Aryl radicals include, but arenot limited to, aryl radicals derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene.

“C₁₋₆aralkyl” means a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike.

“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromaticmonocyclic or polycyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, which may include fused or bridged ring systems,having from three to fifteen carbon atoms, preferably having from threeto ten carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. Monocyclic radicalsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl,and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“C₁₋₆haloalkyl” refers to a C₁₋₆alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike.

“Heterocycle” or “heterocyclyl” means a 4- to 7-membered monocyclic, or7- to 10-membered bicyclic, heterocyclic ring which is either saturated,unsaturated or aromatic, and which contains from 1 to 4 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and wherein thenitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen heteroatom may be optionally quaternized, including bicyclicrings in which any of the above heterocycles are fused to a benzenering. The heterocycle may be attached via any heteroatom or carbon atom.An aromatic heterocycle is referred to herein as a “heteroaryl”, andincludes (but is not limited to) furyl, benzofuranyl, thiophenyl,benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl,quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl,pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,cinnolinyl, phthalazinyl, oxadiazolyl, thiadiazolyl, benzisoxazolyl,triazolyl, tetrazolyl, indazolyl and quinazolinyl. In addition to theheteroaryls listed above, heterocycles also include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, and the like. Inaddition, heterocycles also include benzothiophen-2-yl,2,3-dihydrobenzo-1,4-dioxin-6-yl, benzo-1,3-dioxol-5-yl and the like.

The term “substituted” as used herein (for example, in the context of asubstituted heterocyclyl or substituted aryl) means that at least onehydrogen atom is replaced with a substituent. “Substituents” within thecontext of this invention include halogen, hydroxy, oxo, cyano, nitro,imino, thioxo, amino, alkylamino, dialkylamino, alkyl, alkoxy,alkylthio, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,heterocycle and heterocyclealkyl, as well as —NR_(a)R_(b),—NR_(a)C(═O)R_(b), —NR_(a)C(═O)NR_(a)NR_(b),—NR_(a)C(═O)OR_(b)—NR_(a)SO₂R_(b), —C(═O)R_(a), —C(═O)OR_(a),—C(═O)NR_(a)R_(b), —OC(═O)NR_(a)R_(b), —OR_(a), —SR_(a), —SOR_(a),—S(═O)₂R_(a), —OS(═O)₂R_(a), —S(═O)₂OR_(a), ═NSO₂R_(a) and—SO₂NR_(a)R_(b). In the foregoing, R_(a) and R_(b) in this context maybe the same or different and independently hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocyclyl. In addition, the foregoingsubstituents may be further substituted with one or more of the abovesubstituents.

In further embodiments of structure (I), the compound has the followingstructure (I-A):

In other further embodiments of structure (I), the compound has thefollowing structure (I-B):

In other further embodiments of structure (I), the compound has thefollowing structure (I-C):

In other further embodiments of structure (I), the compound has thefollowing structure (I-D):

In other further embodiments of structure (I), the compound has thefollowing structure (I-E):

In other further embodiments of structure (I), the compound has thefollowing structure (I-F):

In other further embodiments of structure (I), the compound has thefollowing structure (I-G):

In other further embodiments of structure (I), the compound has thefollowing structure (I-H):

In other further embodiments of structure (I), the compound has thefollowing structure (I-I):

In other further embodiments of structure (I), in particular, structures(I-B) and (I-C), R₄ is hydrogen or R₄ is C₁₋₆alkyl (such as, forexample, methyl).

In other further embodiments of structure (I), R₁ is C₁₋₆alkyl (such as,for example, R₁ is methyl or ethyl).

In other further embodiments of structure (I), R₃ is substituted orunsubstituted phenyl (such as, for example, 4-bromo-3,5-dimethoxyphenyl,4-chloro-3,5-dimethoxyphenyl or 3,4,5-trimethoxyphenyl).

In other further embodiments of structure (I), R₂ is substituted orunsubstituted aryl, such as substituted or unsubstituted phenyl. In morespecific embodiments, wherein R₂ is substituted phenyl, R₂ is phenylsubstituted with C₁₋₆alkoxy, or R₂ is phenyl substituted withsubstituted or unsubstituted heterocyclyl (such as, for example,4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl,4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl or 4-morpholinophenyl).

In other further embodiments of structure (I), R₂ is substituted orunsubstituted heterocyclyl.

The compounds of the present invention may generally be utilized as thefree acid or free base. Alternatively, the compounds of this inventionmay be used in the form of acid or base addition salts. Acid additionsalts of the free amino compounds of the present invention may beprepared by methods well known in the art, and may be formed fromorganic and inorganic acids. Suitable organic acids include maleic,fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic,trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric,gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic,glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acidsinclude hydrochloric, hydrobromic, sulfuric, phosphoric, and nitricacids. Base addition salts included those salts that form with thecarboxylate anion and include salts formed with organic and inorganiccations such as those chosen from the alkali and alkaline earth metals(for example, lithium, sodium, potassium, magnesium, barium andcalcium), as well as the ammonium ion and substituted derivativesthereof (for example, dibenzylammonium, benzylammonium,2-hydroxyethylammonium, and the like). Thus, the term “pharmaceuticallyacceptable salt” of structure (I) is intended to encompass any and allacceptable salt forms.

In addition, prodrugs are also included within the context of thisinvention. Prodrugs are any covalently bonded carriers that release acompound of structure (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound. Prodrugs include,for example, compounds of this invention wherein hydroxy, amine orsulfhydryl groups are bonded to any group that, when administered to apatient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus,representative examples of prodrugs include (but are not limited to)acetate, formate and benzoate derivatives of alcohol and aminefunctional groups of the compounds of structure (I). Further, in thecase of a carboxylic acid (—COOH), esters may be employed, such asmethyl esters, ethyl esters, and the like.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of structure (I) beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction, or binding affinity to pharmacologically important site ofaction. Certain isotopically-labelled compounds of structure (I), forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof structure (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

With regard to stereoisomers, the compounds of structure (I) may havechiral centers and may occur as racemates, racemic mixtures and asindividual enantiomers or diastereomers. All such isomeric forms areincluded within the present invention, including mixtures thereof.Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention. In addition, some of the compounds of structure (I) may alsoform solvates with water or other organic solvents. Such solvates aresimilarly included within the scope of this invention.

In another embodiment of the invention, pharmaceutical compositionscontaining one or more compounds of structure (I) are disclosed. For thepurposes of administration, the compounds of the present invention maybe formulated as pharmaceutical compositions. Pharmaceuticalcompositions of the present invention comprise one or more compounds ofthe present invention and a pharmaceutically acceptable carrier and/ordiluent. The PDE10 inhibitor is present in the composition in an amountwhich is effective to treat a particular disorder—that is, in an amountsufficient to achieve desired PDE10 inhibition, and preferably withacceptable toxicity to the warm-blooded animal. Typically, thepharmaceutical compositions of the present invention may include a PDE10inhibitor in an amount from 0.1 mg to 250 mg per dosage depending uponthe route of administration, and more typically from 1 mg to 60 mg.Appropriate concentrations and dosages can be readily determined by oneskilled in the art.

In general terms, a typical daily dosage might range from about 1 μg/kgto 100 mg/kg, preferably 0.01-100 mg/kg, more preferably 0.1-70 mg/kg,depending on the type and severity of the disease whether, for example,by one or more separate administrations. For repeated administrationsover several days or longer, depending on the condition, the treatmentis sustained until a desired suppression of disease symptoms occurs.However, other dosage regimens may be useful. The progress of thistherapy can be monitored by standard techniques and assays. Thespecification for the dosage unit forms of the invention are dictated byand directly dependent on the unique characteristics of the activecompound and the particular therapeutic effect to be achieved, and thelimitations inherent in the art of compounding such an active compoundfor the treatment of individuals.

Pharmaceutically acceptable carrier and/or diluents are familiar tothose skilled in the art. For compositions formulated as liquidsolutions, acceptable carriers and/or diluents include saline andsterile water, and may optionally include antioxidants, buffers,bacteriostats and other common additives. The compositions can also beformulated as pills, capsules, granules, or tablets which contain, inaddition to a PDE10 inhibitor, diluents, dispersing and surface activeagents, binders, and lubricants. One skilled in this art may furtherformulate the PDE10 inhibitor in an appropriate manner, and inaccordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co.,Easton, Pa. 1990.

In another embodiment, the present invention provides a method fortreating diseases such as (but not limited to) psychotic disorders,anxiety disorders, movement disorders and/or neurological disorders suchas Parkinson's disease, Huntington's disease, Alzheimer's disease,encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy,sleep disorders, pain, Tourette's syndrome, schizophrenia, delusionaldisorders, bipolar disorders, post-traumatic stress disorders,drug-induced psychosis, panic disorders, obsessive-compulsive disorders,attention-deficit disorders, disruptive behavior disorders, autism,depression, dementia, cognitive disorders, epilepsy, insomnias andmultiple sclerosis as discussed above. Such methods includeadministering of a compound of the present invention to a warm-bloodedanimal in an amount sufficient to treat the condition. In this context,“treat” includes prophylactic administration. Such methods includesystemic administration of a PDE10 inhibitor of this invention,preferably in the form of a pharmaceutical composition as discussedabove. As used herein, systemic administration includes oral andparenteral methods of administration, including subcutaneous,intramuscular, intracranial, intraorbital, ophthalmic, intraventricular,intracapsular, intraarticular, intraspinal, intracisternal,intraperitoneal, intranasal, aerosol, intravenous, intradermal,inhalational, transdermal, transmucosal, and rectal administration.

For oral administration, suitable pharmaceutical compositions of PDE10inhibitors include powders, granules, pills, tablets, and capsules aswell as liquids, syrups, suspensions, and emulsions. These compositionsmay also include flavorants, preservatives, suspending, thickening andemulsifying agents, and other pharmaceutically acceptable additives andexcipients. For parenteral administration, the compounds of the presentinvention can be prepared in aqueous injection solutions which maycontain, in addition to the PDE10 inhibitor, buffers, antioxidants,bacteriostats, and other additives and excipients commonly employed insuch solutions. Compositions of the present invention may be carried ina delivery system to provide for sustained release or enhanced uptake oractivity of the therapeutic compound, such as a liposomal or hydrogelsystem for injection, a microparticle, nanopartical or micelle systemfor oral or parenteral delivery, or a staged capsule system for oraldelivery.

In a further advantage of the present invention, compounds of structure(I) are expected to avoid or reduce metabolic side effects associatedwith conventional antipsychotics, in particular the incidence oftherapeutically induced obesity. For example, chronic use of olanzapine(Zyprexa®), the most widely prescribed medication to treatschizophrenia, and related atypical antipsychotics is associated withsignificant metabolic side effects including obesity and associatedconditions such as diabetes.

In animals, subchronic treatment with olanzapine stimulates food intakeand increases body weight, consistent with human situations.Furthermore, olanzapine acutely lowers blood leptin levels. Leptin is asatiety hormone produced from adipose tissues, and decrease of leptinlevel stimulates appetite. It is theorized that olanzapine couldstimulate food intake at least partly by reducing leptin levels. Acuteadministration of olanzapine also changes the animal's response inglucose and insulin levels in glucose tolerance tests, which may also bedirectly linked to olanzapine's effect in food intake and body weightgain. Examination of the acute effect of PDE10 inhibitors of the presentinvention on metabolism, such as leptin, insulin and glucose changesduring a metabolic challenge in standard animal models, as well as thechronic effect of PDE10 inhibitors of the present invention in foodintake, body weight and energy homeostasis, in comparison witholanzapine should provide evidence to the pharmaceutical advantage ofPDE10 inhibitors as antipsychotics in terms of less side-effectconcerns.

The compositions of the present invention may be administered incombination with one or more additional therapeutic agents, incombination or by concurrent or sequential administration. Suitableadditional agents (i.e., adjuvants) may include typical antipsychoticsthat block dopamine-D₂ receptors and serotonin 5HT₂ receptors, e.g.,haloperidol, fluphenazine, chlorpromazine, and atypical antipsychotics,e.g., clozapine, olanzapine, risperidone, quetiapine, ziprasidone.

Compounds of this invention may be assayed to determine their IC₅₀values by a modification of the two-step method of Thompson and Appleman(Biochemistry 10; 311-316; 1971). In short, cAMP is spiked with (³H)cAMPand incubated with PDE10 and various concentrations of a compound ofstructure (I). After the appropriate incubation time, the reaction isterminated by heating. The mixture is then subjected to treatment withsnake venom phosphatase. The phosphatase hydrolyzes any AMP in themixture, but leaves unreacted cAMP intact. Thus, by separating cAMP fromthe mixture and determining its concentration (by radiography), thepercent of inhibition can be determined. IC₅₀ values can be calculatedby performing the experiment at several concentrations using standardgraphical means. A detailed description of the actual technique used forIC₅₀ assays as set forth in following Examples. To this end, PDE10inhibitors of the invention have an IC₅₀ of 100 μM or less, generallyless than 10 μM, and typically less than 1 μM.

The compounds of the present invention may be prepared by known organicsynthesis techniques, including the methods described in more detail inthe following examples. The following examples are provided for purposesof illustration, not limitation.

EXAMPLES Example 11-(4-(4-Bromo-3,5-Dimethoxyphenyl)Thiazol-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

An oven-dried flask was charged with 4-(4-morpholinyl)benzaldehyde (10.1g, 53 mmol), anhydrous methanol (60 mL) and anhydrous dioxane (60 mL)then fitted with an addition funnel. The addition funnel was chargedwith a solution of KOH (14.8 g, 264 mmol) in anhydrous methanol (60 mL)and an aliquot (˜2 mL) was added to the reaction mixture. Bromoform (5.8mL, 67.1 mmol) was added to the reaction mixture then the remainingKOH/MeOH solution was added dropwise over 10 minutes. After stirring for18 h, the mixture was filtered through Celite and rinsed with methanol.The filtrate was collected and concentrated in vacuo. The residue wasthen diluted with saturated aqueous NH₄Cl and extracted with EtOAc.Additional EtOAc was then used to extract the aqueous phase while slowlyadjusting the pH from ˜8 to ˜2 using concentrated HCl. A total ofapproximately 1.5 L of EtOAc was used for the extraction process. Thecombined EtOAc extracts were dried over Na₂SO₄ and filtered.Concentration of the filtrate in vacuo gave2-methoxy-2-(4-morpholinophenyl)acetic acid as a tan solid (7.25 g,58%).

To a suspension of 2-methoxy-2-(4-morpholinophenyl)acetic acid (2.97 g,11.8 mmol) in anhydr. CH₂Cl₂ (66 mL) in an oven-dried flask under argonwas added N-methylmorpholine (3 mL, 27.3 mmol) and the resultingsolution was cooled over ice. Isobutylchloroformate (1.8 mL, 13.76 mmol)was added dropwise. After stirring for 50 min, N,O-dimethylhydroxylaminehydrochloride (1.5 g, 15.3 mmol) was added and the mixture was allowedto warm slowly to room temp. After stirring for 16 hours, saturatedaqueous NaHCO₃ was added and the mixture stirred for >15 min. Themixture was diluted with CH₂Cl₂ and the layers were separated. Theorganics were washed with brine, dried over MgSO₄/Na₂SO₄ andconcentrated. Purification by chromatography (60-85% EtOAc-hexanes) gaveN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl) acetamide as an off-whitesolid (3.15 g, 90% yield).

An oven-dried flask under argon was charged with4-bromo-3,5-dimethoxybenzaldehyde (10.08 g, 41.1 mmol) and anhydrous THF(70 mL). The mixture was cooled over a −78° C. bath then a solution ofMeMgBr (3.0 M in diethyl ether, 17.8 mL, 53.4 mmol) was added dropwisefrom an addition funnel over a period of 45 min. After stirring for 20min, the mixture was allowed to warm to room temperature and stirred for19 hours. After quenching with a solution of aqueous NH₄Cl, it wasdiluted with H₂O and EtOAc then cooled over an ice bath. After themixture was cooled, the layers were separated. The organics were washedwith H₂O and brine then dried over Na₂SO₄ and concentrated in vacuo. Theresidue was dissolved in dichloromethane and concentrated in vacuo againto give 1-(4-bromo-3,5-dimethoxyphenyl)ethanol as a white solid (10.8 g,quantitative yield). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanol (10.8 g, 41.1mmol) in anhydrous CH₂Cl₂ (150 mL) was added MnO₂ (48 g, 552 mmol).After the mixture was placed under a drying tube and stirred at roomtemperature for 22 hours, it was filtered through a pad of Celite andsilica gel and rinsed with EtOAc. Concentration of the filtrate in vacuogave 1-(4-bromo-3,5-dimethoxyphenyl)ethanone as a white solid (10.3 g,97% yield). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.895 g, 3.45mmol) in anhydrous CH₂Cl₂ (5 mL) under a drying tube was added a freshlymade solution of Br₂ in CH₂Cl₂ (1.95 M, 1.9 mL, 3.7 mmol) dropwise. Thereaction was stirred at room temperature for 30 min then neutralizedwith a solution of saturated aqueous NaHCO₃. The mixture was dilutedwith CH₂Cl₂ and the layers were separated. The organics were washed withsaturated aqueous NaHCO₃ and brine then dried over MgSO₄/Na₂SO₄ andconcentrated in vacuo. The crude product was adsorbed onto silica gel(2.9 g) as a CH₂Cl₂ solution. Purification by chromatography (0-20%EtOAc-hexanes) gave 2-bromo-1-(4-bromo-3, 5-dimethoxyphenyl)ethanone asa white solid (0.737 g, 63% yield). Large-scale synthesis of2-bromo-1-(4-bromo-3, 5-dimethoxyphenyl)ethanone was performed withoutchromatographic purification of the bromide.

An oven-dried flask under argon was charged with P₂S₅ (0.53 g, 1.2mmol), anhydrous dioxane (5 mL), and formamide (0.53 mL, 13.3 mmol). Thereaction flask was fitted with a reflux condenser and a drying tube andrefluxed for 2.25 hours. A separate oven-dried flask under argon wascharged with 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.313 g,0.93 mmol) and anhydrous dioxane (6 mL). The thioformamide mixture(above) was decanted into the reaction flask leaving solids behind. Thereaction flask was fitted with a reflux condenser, put under a dryingtube and refluxed for 3 hours then cooled to room temp. After stirringovernight, the mixture was made basic with the addition of an aqueoussolution of 2 M Na₂CO₃, diluted with H₂O then extracted with EtOAc threetimes. The combined organics were washed with brine, dried over Na₂SO₄and concentrated. The crude solid was dissolved in CH₂Cl₂ and adsorbedonto silica gel. Purification by chromatography (0-35% EtOAc-hexanes)gave 4-(4-bromo-3,5-dimethoxyphenyl)thiazole as a white solid (0.20 g,73% yield).

To a −78° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0.096g, 0.32 mmol) in anhydrous THF (2 mL) under argon was added a solutionof LiHMDS (1.0 M in THF, 0.35 mmol) dropwise. After stirring for 30 min,a solution of N, 2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide(0.121 g, 0.41 mmol) in anhydrous THF (1.5 mL, 1.0 mL) was addeddropwise. After stirring for 35 min, the cold bath was removed and thereaction was allowed to warm to room temp. The mixture was quenched withbrine and diluted with EtOAc. The layers were separated and the organiclayer was washed with brine, dried over Na₂SO₄ and concentrated.Purification by chromatography (25-45% EtOAc-hexanes) gave1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanoneas a yellow solid (0.050 g, 29% yield). MS: m/z 533.1 [M+H]⁺.

Example 21-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)-Ethanone

A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)ethanone (0.8 g,0.96 mmol) in formamide (7 mL) in an oven-dried flask under argon washeated at 100° C. for 10 hours then 110° C. for 5 hours. After coolingto room temp, EtOAc and saturated aqueous NaHCO₃ were carefully addedand the mixture was stirred for 15 minutes. It was then extracted withEtOAc twice and the combined organics were washed with H₂O and brine,dried over Na₂SO₄ and concentrated. Purification by chromatography(20-40% EtOAc-hexanes) provided 4-(4-bromo-3,5-dimethoxyphenyl)oxazoleas a yellow solid (0.387 g, 58% yield).

To a −20° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)oxazole (0.158g, 0.56 mmol) in anhydrous THF (2 mL) in an oven-dried flask under argonwas added a solution of LDA (2.0 M in THF/heptane/ethylbenzene; 0.37 mL,0.74 mmol) dropwise. The mixture was stirred at −20 to −10° C. for 50min then cooled to −20° C. A solution ofN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.245 g, 0.83mmol) in anhydrous THF (3 mL) was added then the mixture was allowed toslowly warm to room temperature and stirred for a total of 21 hours. Thereaction mixture was quenched with H₂O and extracted with EtOAc. Thecombined organics were washed with brine, dried over Na₂SO₄ andconcentrated. Purification by chromatography (50-60% EtOAc-hexanes)provided1-(4-(4-bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)-ethanoneas a yellow solid (0.097 g, 34% yield). MS: m/z 517.1 [M+H]⁺.

Example 32-(4-(1H-Pyrazol-1-Yl)Phenyl)-1-(4-(4-Bromo-3,5-Dimethoxyphenyl)Thiazol-2-Yl)-2-Methoxyethanone

To a stirred solution of 4-(1H-pyrazol-1-yl)benzaldehyde (1.3 g, 7.55mmol) and bromoform (0.85 mL, 9.75 mmol) in MeOH (10 mL) and dioxane (10mL) was added dropwise a solution of potassium hydroxide (2.2 g, 39mmol) in MeOH (10 mL) over 15 minutes. Stirring was then continued for23 hours. The mixture was filtered through Celite, rinsed through withEtOAc and concentrated under reduced pressure to yield potassium2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate as a light yellow solid(3.2 g) that was used without further purification. See U.S. Pat. No.7,129,238.

To a stirred solution of potassium2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate (˜7.55 mmol) in dry MeOHunder argon was added sulfuric acid (2.0 mL) dropwise. The mixture washeated at 80° C. for 17 hours. After cooling to room temperature, waterwas added then the mixture made basic with saturated aqueous NaHCO₃addition. The aqueous phase was extracted with EtOAc and the combinedorganics were washed with water and brine then dried over Na₂SO₄ andconcentrated in vacuo. Purification by chromatography (20-35%EtOAc-hexanes) provided methyl2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate as a colorless oil (0.88g, 47% yield for two steps).

To a stirred solution of methyl2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate (0.204 g, 0.83 mmol) indry MeOH (5 mL) under argon was added a solution of KOH in MeOH (1.6 mLof a 0.5 M solution, 8.3 mmol) and the reaction was heated to reflux for5 hours. The reaction mixture was cooled to room temperature and thevolatiles were removed under reduced pressure. The residue was dilutedwith saturated aqueous NH₄Cl and extracted with EtOAc. Additional EtOAcwas then used to extract the aqueous phase as the pH was adjusted from˜8 to ˜2 using concentrated HCl. The combined organics were dried overNa₂SO₄, filtered, and the solvents removed under reduced pressure toyield 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetic acid (0.18 g, 95%)which was used without further purification.

To a solution of methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyaceticacid (0.18 g, 0.77 mmol) in dry dichloromethane (5 mL) under argon wasadded N-methylmorpholine (0.18 mL, 1.7 mmol). The reaction mixture wascooled to 0° C., isobutylchloroformate was added, (0.11 mL, 0.85 mmol)and the mixture was stirred for 40 minutes. N, O-dimethylhydroxylaminehydrochloride (0.098 g, 1 mmol) was then added in one portion and slowlyallowed to warm to room temperature and stirred for 18 hours. Themixture was diluted with saturated aqueous NaHCO₃ and extracted withEtOAc. The combined organics were washed with brine, dried over Na₂SO₄and concentrated in vacuo. Purification by chromatography (0-80%EtOAc-hexanes) provided2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.16 g,76% yield).

To a −20° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0.092g, 0.305 mmol) in anhydrous THF (2 mL) under argon was added a solutionof LDA (0.18 mL of a 2.0 M solution in THF/heptane/ethylbenzene, 0.37mmol) dropwise. After stirring for 30 min, the reaction was cooled to−78° C. and a solution of2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.15 g,0.55 mmol) in anhydrous THF (1.5 mL, 1.0 mL) was added dropwise. Afterstirring for 90 min, the mixture was quenched with brine and dilutedwith EtOAc. The layers were separated and the organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. Purification bychromatography (0-35% EtOAc-hexanes) gave2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxyethanoneas a yellow solid (0.030 g, 20% yield). MS: m/z 514.0 [M+H]⁺.

Example 41-(4-(4-Bromo-3,5-Dimethoxyphenyl)-1-Methyl-1H-Imidazol-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

To an oven-dried flask under argon was added4-bromo-3,5-dimethoxybenzaldehyde (1.0 g, 4.08 mmol), absolute EtOH (34mL), p-toluenesulfonylmethyl isocyanide (0.78 g, 4.0 mmol) and KCN(0.035 g, 0.54 mmol). The mixture was stirred for 19 hours at roomtemperature then concentrated in vacuo to give5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl-4,5-dihydrooxazole which wasused in the next synthetic step without purification.

To an oven-dried pressure tube was added5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl-4,5-dihydrooxazole (0.4 g, 0.91mmol), methylamine-THF solution (1.8 mL of a 2.0 M solution, 3.6 mmol),and xylenes (5 mL). The tube was sealed under argon then heated at 135°C. for 15 hours. After cooling to room temperature, the reaction mixturewas transferred and concentrated in vacuo then partitioned between EtOAcand H₂O. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organics were washed with brine twice, driedover Na₂SO₄ and concentrated. Purification by chromatography (50-100%EtOAc-hexanes then 2-5% MeOH-EtOAc) provided4-(4-bromo-3,5-dimethoxyphenyl)-1-methyl-1H-imidazole as a light yellowsolid (0.056 g, 21% yield).

The method used for the final coupling step of Example 3 was used withmodification. The reaction was allowed to warm to room temperatureovernight. Purification by chromatography (40-55% EtOAc-hexanes)provided1-(4-(4-bromo-3,5-dimethoxyphenyl)-1-methyl-1H-imidazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone (0.0039 g, 4% yield). MS: m/z 530.1 [M+H]⁺.

Example 52-(4-(1H-Pyrazol-1-Yl)Phenyl)-1-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxyethanone

2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxyethanone was synthesized from2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide and4-(4-bromo-3,5-dimethoxyphenyl)oxazole by a method similar to that usedfor Example 2 except that the amide was added to the reaction mixture at−50° C. MS: m/z 498.1 [M+H]⁺.

Example 61-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxy-2-(4-(Piperidin-1-Yl)Phenyl)Ethanone

N,2-dimethoxy-N-methyl-2-(4-(piperidin-1-yl)phenyl)acetamide wassynthesized in two steps from 4-(piperidin-1-yl)benzaldehyde followingthe method used for Example 1.1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-(piperidin-1-yl)phenyl)ethanonewas synthesized fromN,2-dimethoxy-N-methyl-2-(4-(piperidin-1-yl)phenyl)acetamide and4-(4-bromo-3, 5-dimethoxyphenyl)oxazole following the method used forExample 5. MS: m/z 515.1 [M+H]⁺.

Example 71-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxy-2-(4-(Pyrrolidin-1-Yl)Phenyl)Ethanone

N,2-dimethoxy-N-methyl-2-(4-(pyrrolidin-1-yl)phenyl)acetamide wassynthesized from 4-(pyrrolidin-1-yl)benzaldehyde following the methodused for the synthesis of Example 1.1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-(pyrrolidin-1-yl)phenyl)ethanonewas synthesized fromN,2-dimethoxy-N-methyl-2-(4-(pyrrolidin-1-yl)phenyl)acetamide and4-(4-bromo-3,5-dimethoxyphenyl)oxazole following the method used forExample 2 except that the amide was added to the reaction mixture at−45° C. MS: m/z 501.1 [M+H]⁺.

Example 81-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-(4-Isopropoxyphenyl)-2-Methoxyethanone

An oven-dried flask was charged with 4-isopropoxybenzaldehyde (4.9 g,29.9 mmol), anhydrous methanol (30 mL) and anhydrous dioxane (30 mL)then fitted with an addition funnel. The addition funnel was chargedwith a solution of KOH (8.4 g, 149.5 mmol) in anhydrous methanol (30 mL)and an aliquot (˜2 mL) was added to the reaction mixture. Bromoform (3.4mL, 38.8 mmol) was added to the reaction mixture then the remainingKOH/MeOH solution was added dropwise over 10 minutes. After stirring for18 hours, the mixture was concentrated in vacuo. The residue was dilutedwith water and the pH was adjusted to ˜2 using concentrated HCl thenextracted with EtOAc. The combined organics were dried over Na₂SO₄ andfiltered. Concentration of the filtrate in vacuo gave2-(4-isopropoxyphenyl)-2-methoxyacetic acid as a light yellow solid (6.8g) which was used without further purification.

2-(4-Isopropoxyphenyl)-N,2-dimethoxy-N-methylacetamide was synthesizedfrom 2-(4-isopropoxyphenyl)-2-methoxyacetic acid following the methodused for the synthesis of Example 1.1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl-2-(4-isopropoxyphenyl)-2-methoxyethanonewas synthesized from2-(4-isopropoxyphenyl)-N,2-dimethoxy-N-methylacetamide and4-(4-bromo-3,5-dimethoxyphenyl)oxazole following the method used for thesynthesis of Example 7. MS: m/z 490.1 [M+H]⁺.

Example 91-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxy-2-(Quinolin-5-Yl)Ethanone

N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide was synthesized fromquinoline-5-carbaldehyde in two steps following the method used for thesynthesis of Example 1.1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(quinolin-5-yl)ethanonewas synthesized from N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamideand 4-(4-bromo-3,5-dimethoxyphenyl)oxazole following the method used forExample 2. MS: m/z 483.0 [M+H]⁺.

Example 101-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxy-2-(Quinolin-3-Yl)Ethanone

N,2-dimethoxy-N-methyl-2-(quinolin-3-yl)acetamide was synthesized fromquinoline-3-carbaldehyde in two steps following the method used for thesynthesis of Example 1.1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(quinolin-3-yl)ethanonewas synthesized from N,2-dimethoxy-N-methyl-2-(quinolin-3-yl)acetamideand 4-(4-bromo-3, 5-dimethoxyphenyl)oxazole following the method usedfor Example 2. MS: m/z 483.1 [M+H]⁺.

Example 111-(4-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamidewas synthesized from 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde intwo steps following the method used for the synthesis of Example 1.1-(4-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas synthesized fromN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideand 4-(4-bromo-3,5-dimethoxyphenyl)oxazole following the method used forExample 2 except that the amide was added to the reaction mixture at−30° C. MS: m/z 514.0 [M+H]⁺.

Example 121-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

To a flask containing a suspension of 4-bromo-3,5-dimethoxyaniline (1.99g, 8.56 mmol; synthesized according to US2006/128695) in H₂O (60 mL) wasslowly added concentrated H₂SO₄ (10 mL). The exotherm was controlled bycooling over ice then the reaction was cooled to −10 to −8° C. (bathtemperature). After a solution of NaNO₂ (0.70 g, 10 mmol) in H₂O (3.5mL) was added dropwise over a period of 6 min, the mixture was stirredfor 70 min. A solution of KI (2.8 g, 16.9 mmol) in H₂O (3.5 mL) wasadded dropwise and the mixture was stirred at −10 to −5° C. for 30 min.After the cold bath was removed, the mixture was stirred for 80 min thenEtOAc was added and the mixture stirred for an additional 40 min. Thelayers were separated and the aqueous layer was extracted with EtOAcseveral times. The combined organics were washed with 1 M NaOH twice,10% Na₂S₂O₃ twice and brine then dried over Na₂SO₄. Purification bychromatography (0-20% EtOAc-hexanes) provided2-bromo-5-iodo-1,3-dimethoxybenzene (1.86 g, 63% yield).

2-(4-Bromo-3,5-dimethoxyphenyl)furan was synthesized according to theprocedure reported in WO 2008/040669 as follows. To a round bottom flaskcontaining 3,5-dimethoxy-4-bromo-iodobenzene (7.9 g, 85% purity, 19.6mmol), 2-furylboronic acid (3.4 g, 30.4 mmol), triphenylphosphine (0.358g, 1.37 mmol), tetrabutylammonium bromide (7.94 g, 14.6 mmol) and Na₂CO₃(4.9 g, 46.2 mmol) was added THF (87 mL) and H₂O (87 mL). The mixturewas degassed by alternately putting under house vacuum and argon threetimes for several minutes each. 10% Pd/C (1.36 g) was added and themixture was heated at 60° C. for 17 hrs under argon. After cooling toroom temperature, the mixture was filtered through Celite and rinsedwith THF and EtOAc. The filtrate layers were separated and the organiclayer was washed with brine, dried over Na₂SO₄ and concentrated.Purification by column chromatography (0-25% Et₂O-hexanes) gave2-(4-bromo-3,5-dimethoxyphenyl)furan as a white solid (5.06 g, 91%yield). Product TLC Rf 0.35 (15% EtOAc-hexanes TLC eluent).

To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.203 g, 0.72mmol) in anhydrous THF (2 mL) under argon in an oven-dried flask cooledto −78° C. was added a solution of lithium diisopropylamide (2.0 M inTHF/heptane/ethylbenzene; 0.4 mL, 0.8 mmol) dropwise. After stirring for35 min at −78° C., a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.315 g, 1.1 mmol)in THF (2 mL) was added dropwise. After stirring for 25 min, the mixturewas allowed to warm to room temp while stirring for 2 hrs. The reactionwas quenched with the addition of saturated aqueous NH₄Cl then brine andEtOAc were added. The layers were separated and the organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo.Purification by column chromatography (35-65% EtOAc-hexanes) provided anoil that was triturated with MeOH-Et₂O (1:1) with sonication. The solidwas collected on a Buchner, rinsed with MeOH-Et₂O (1:1) and dried invacuo to give1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanoneas a yellow solid. A second batch was collected from MeOH-Et₂O (˜10%) togive additional product (0.220 g total, 59% yield). MS: m/z 516.1[M+H]⁺.

Example 131-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

To a solution of 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (5.12 g,27.2 mmol) in anhydrous MeOH (27 mL) and anhydrous dioxane (27 mL) at−15 to −10° C. (bath temperature) was added several drops of a solutionof KOH (7.6 g, 135.4 mmol) in MeOH (27 mL). Bromoform (3 mL, 34.4 mmol)was added, then the remaining KOH/MeOH solution was added over a periodof 20 min. The mixture was stirred for 1 hr and the cold bath wasremoved. After stirring for 30 min, the reaction was put over an icebath and allowed to warm slowly to room temperature overnight thenconcentrated to dryness. After dissolving in a minimum amount of H₂O,the residue was acidified to pH 1 with 6 M HCl. The aqueous mixture wasextracted with EtOAc several times with the addition of brine to theaqueous layer during extraction. The combined organics were washed withbrine, dried over Na₂SO₄ and concentrated in vacuo to give2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid as asemisolid (6.8 g, quantitative yield). The product was used withoutfurther purification.

To an ice-cold solution of2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid (6.8 g,27.4 mmol) in anhydrous CH₂Cl₂ (270 mL) and diisopropylethylamine (17mL, 97 mmol) under argon was added bis(2-methoxyethyl)aminosulfurtrifluoride (5.6 mL, 30.3 mmol) dropwise. After stirring over an icebath for 45 min, N,O-dimethylhydroxylamine hydrochloride (3.40 g, 34.8mmol) was added in three aliquots over a period of 15 min. The mixturewas stirred for 15 min then the ice bath was removed. After 3 hrs,saturated aqueous NaHCO₃ was added and stirred for 30 min. The layerswere separated and the aqueous layer was extracted with CH₂Cl₂. Thecombined organics were washed with saturated aqueous NaHCO₃, H₂O andbrine, dried over MgSO₄, filtered through Celite and concentrated invacuo. Purification by chromatography (75-100% EtOAc-hexanes then 0-5%EtOH-EtOAc) gaveN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideas an oil that solidified upon standing (2.06 g, 26% yield).

2-(4-Bromo-3,5-dimethoxyphenyl)furan was coupled withN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the method used for the synthesis of Example 12.Purification by chromatography (50-80% EtOAc-hexanes) provided1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanoneas a yellow foam (0.356 g, 40% yield). MS: m/z 513.2 [M+H]⁺.

Example 142-(4-(1H-Pyrazol-1-Yl)Phenyl)-1-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxyethanone

The method used for the final coupling step of Example 12 was used.Purification by chromatography (20-55% EtOAc-hexanes) provided2-(4-(1H-pyrazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanoneas a light yellow solid (0.0625 g, 37% yield). MS: m/z 497.2 [M+H]⁺.

Example 152-(4-(1H-Pyrazol-4-Yl)Phenyl)-1-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxyethanone

To a suspension of 4-bromopyrazole (1.5 g, 10.2 mmol) and4,4′,4″-trimethoxytrityl chloride (4.5 g, 12.2 mmol) in anhydrous DMF(20 mL) under argon was added triethylamine (3 mL, 21.5 mmol) and themixture was cooled over an ice bath. After stirring for 10 min, the icebath was removed and the reaction stirred for 2.5 hrs. The mixture wasdiluted with H₂O and extracted with EtOAc. The combined organics werewashed with H₂O three times then saturated aqueous NaHCO₃ and brine. Thesolution was dried over Na₂SO₄ and concentrated in vacuo. The crude oilwas recrystallized from isopropanol to give4-bromo-1-(tris(4-methoxyphenyl)methyl)-1H-pyrazole as off-whitecrystals (two batches; 2.55 g, 52% yield).

A mixture of 4-bromo-1-(tris(4-methoxyphenyl)methyl)-1H-pyrazole (1.47g, 3.1 mmol), (4-formylphenyl)boronic acid (0.94 g, 6.3 mmol), and K₂CO₃(0.65 g, 4.7 mmol) in DME-H₂O (25 mL, 4:1) was degassed by alternatelyputting under house vacuum and argon three times for several minuteseach. Tetrakis(triphenylphosphine)palladium (0.35 g, 0.3 mmol) was addedthen the mixture was degassed again. After heating for 16.5 hrs at 80°C. and cooling to room temperature, H₂O was added. The mixture wasextracted with EtOAc and the combined organics were washed with H₂O,saturated aqueous NaHCO₃ and brine then dried over Na₂SO₄ andconcentrated in vacuo. Purification by chromatography (20-30%EtOAc-hexanes; EtOAc containing 1% Et₃N) gave4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)benzaldehyde (1.31 gcombined from two reactions, 33%).

The method used for the synthesis of Example 1 was used except that thepotassium salt was isolated. Following the reaction at room temperature,EtOAc was added and the mixture was filtered through Celite andconcentrated in vacuo. The residue was dissolved in EtOAc, filteredthrough Celite and concentrated in vacuo. The product was dissolved inEtOAc-toluene and concentrated to give potassium2-methoxy-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetate(1.75 g, quantitative yield) which was used without furtherpurification.

To an ice-cold solution of potassium2-methoxy-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetate(1.25 g, 2.1 mmol) in anhydrous DMF (10 mL) under argon was addeddiisopropylethylamine (0.54 mL, 3.1 mmol) andbis(2-methoxyethyl)aminosulfur trifluoride (0.46 mL, 2.5 mmol) dropwise.The reaction was stirred for 30 min then N,O-dimethylhydroxylaminehydrochloride (0.303 g, 3.1 mmol) was added. After stirring for afurther 15 min over an ice bath, the mixture was allowed to warm to roomtemperature and stirred for 3.5 hrs. H₂O was added and the mixture wasextracted with EtOAc. The combined organics were washed with H₂O,saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine then driedover Na₂SO₄ and concentrated in vacuo. Purification by chromatography(45-90% EtOAc-hexanes; EtOAc containing 1% Et₃N) to giveN,2-dimethoxy-N-methyl-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)acetamide(0.478 g from two reactions, 32% yield overall).

The method used for the final coupling step of Example 12 was usedexcept with a shorter reaction time at room temperature of 70 min.Purification by chromatography (35-90% EtOAc-hexanes; EtOAc containing1% Et₃N) provided1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)ethanoneas a solid (0.10 g, 18% yield).

To a suspension of1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)ethanone(0.10 g, 0.12 mmol) in MeOH—H₂O (22 mL, 10:1) was added pyridiniumpara-toluenesulfonate (0.046 g, 0.16 mmol). After stirring for 18 hrs atroom temperature, saturated aqueous NaHCO₃ was added and the volatileswere removed in vacuo. The residue was diluted with a small amount ofH₂O then extracted with EtOAc. The combined organics were washed withH₂O and brine, dried over Na₂SO₄ and concentrated in vacuo. Purificationby chromatography (50-100% EtOAc-hexanes) provided2-(4-(1H-pyrazol-4-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanoneas a yellow foam (0.010 g, 17% yield). MS: m/z 497.0 [M+H]⁺.

Example 161-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methylfuran-2-Yl)Phenyl)Ethanone

2-Methoxy-2-(4-(5-methylfuran-2-yl)phenyl)acetic acid was synthesizedfrom 4-(5-methylfuran-2-yl)benzaldehyde using the method described forExample 1 (3.3 g, quantitative yield). The product was used withoutfurther purification.

N,2-Dimethoxy-N-methyl-2-(4-(5-methylfuran-2-yl)phenyl)acetamide wassynthesized from 2-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)acetic acidfollowing the method used for Example 13. The product was isolated as anorange oil (0.693 g, 18% yield).

2-(4-Bromo-3,5-dimethoxyphenyl)furan was coupled withN,2-dimethoxy-N-methyl-2-(4-(5-methylfuran-2-yl)phenyl)acetamidefollowing the method used for the final coupling step of Example 12.Purification by chromatography (30-60% EtOAc-hexanes) provided1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)ethanoneas a pale orange colored solid (0.172 g, 47% yield). MS: m/z 511.0[M+H]⁺.

Example 172,3-Dimethoxy-5-(5-(2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Acetyl)Furan-2-Yl)Benzonitrile

To a mixture of 5-bromo-2,3-dimethoxybenzonitrile (0.958 g, 4.0 mmol),2-furylboronic acid (0.53 g, 4.7 mmol), dioxane (24 mL), H₂O (8 mL) andNa₂CO₃ (1.1 g, 10.4 mmol) was addedtetrakis(triphenylphosphine)palladium (0.23 g, 0.2 mmol). The mixturewas degassed by alternately putting under house vacuum and argon threetimes for several minutes each then heated at 85° C. under argon for16.5 hrs. After cooling to room temperature, the mixture was dilutedwith H₂O and extracted with EtOAc. The combined organics were washedwith H₂O and brine, dried over Na₂SO₄ and concentrated in vacuo.Purification by chromatography (0-20% EtOAc-hexanes) provided5-(furan-2-yl)-2,3-dimethoxybenzonitrile as a white solid (0.85 g, 94%yield).

The method used for the final coupling step of Example 12 was followedfor the reaction of 5-(furan-2-yl)-2,3-dimethoxybenzonitrile andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideexcept that the reaction was performed at −40 to −25° C. then warmed toroom temperature. Purification by chromatography (20-100% EtOAc-hexanes)provided2,3-dimethoxy-5-(5-(2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetyl)furan-2-yl)benzonitrile(0.040 g, 13% yield). MS: m/z 460.2 [M+H]⁺.

Example 181-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-(4-(5-Ethyl-1,3,4-Oxadiazol-2-Yl)Phenyl)-2-Methoxyethanone

To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzohydrazide(6.0 g, 21.4 mmol; reported in Tanaka, A. et al. J. Med. Chem. 1998, 41,2390) and ethyl propionimidate hydrochloride (3.5 g, 25.7 mmol;preparation reported in WO2007/73299 A1) in EtOH (120 mL) was added Et₃N(2.59 g, 25.7 mmol). The mixture was stirred at room temperature for 1hr then concentrated in vacuo. The residue was partitioned into EtOAcand H₂O and the organics were washed with H₂O and brine, dried overNa₂SO₄ and concentrated in vacuo. Purification by chromatography(EtOAc-hexanes) gave2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazoleas a brown oil (3.0 g, 44% yield).

To an ice-cold solution of2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazole(3.0 g, 9.4 mmol) in MeOH (30 mL) was added 1 M HCl (20 mL, 20 mmol)dropwise. The reaction was stirred over ice for 1 hr then concentrated.The residue was quenched with saturated aqueous NaHCO₃ and extractedwith EtOAc. The combined organics were dried over Na₂SO₄ andconcentrated in vacuo to give(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)methanol as an off-white solid(1.92 g, 93% yield).

To a solution of (4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)methanol (1.8g, 8.8 mmol) in CH₂Cl₂ (50 mL) was added molecular sieves (1.5 g, 4 Å)and the mixture was cooled to 0° C. Pyridinium chlorochromate (2.27 g,10.5 mmol) was added in portions to the reaction mixture then it waswarmed to room temperature. After stirring for 2 hrs, the mixture wasfiltered through Celite and rinsed with additional CH₂Cl₂. The filtratewas concentrated in vacuo. Purification by chromatography(EtOAc-hexanes) provided 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde asan off-white solid (1.3 g, 70%).

To a solution of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde (1.6 g,7.9 mmol) in anhydr DMF (7 mL) was added CHCl₃ (2.13 g, 17.8 mmol).After cooling to −10° C., a solution of KOH (0.31 g, 5.5 mmol) in anhydrMeOH (1.5 mL) was added dropwise over 20 min. After stirring at −10° C.for 1 hr, the reaction mixture was quenched with 1 M HCl. The solidformed was collected on a Buchner, washed with H₂O and dried undervacuum to give2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol as awhite solid (2.0 g, 80% yield).

To a solution of2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol (2.0g, 6.25 mmol) in anhydr 1,4-dioxane (12.5 mL) and anhydr MeOH (15 mL)was added a solution of NaOH (1.25 g, 31.3 mmol) in anhydr MeOH (15 mL).After stirring for 4 hrs at 55° C., the mixture was cooled to roomtemperature and concentrated in vacuo. The residue was neutralized withsaturated aqueous NH₄Cl, acidified carefully with 1 M HCl and extractedwith EtOAc. The combined organics were dried over Na₂SO₄ andconcentrated in vacuo. The residue was triturated with Et₂O to give2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyacetic acid as anoff-white solid (1.2 g, 73% yield).

The method used for the synthesis of Example 1 was followed for thesynthesis of2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamidefrom 2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyacetic acid.Purification by chromatography (20% EtOAc-hexanes) gave2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamideas an amorphous solid (0.55 g, 40% yield).

The method used for the final coupling step of Example 12 was followedfor the reaction of 2-(4-bromo-3,5-dimethoxyphenyl)furan with2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide.Purification by chromatography (20-100% EtOAc-hexanes) gave1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanoneas a yellow foam (0.037 g, 12% yield). MS: m/z 527.1 [M+H]⁺.

Example 191-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-(4-(1,1-Dioxidoisothiazolidin-2-Yl)Phenyl)-2-Methoxyethanone

The method used for the synthesis of Example 1 was followed for thesynthesis of 2-methoxy-2-(4-nitrophenyl)acetic acid from4-nitrobenzaldehyde. The acid isolated after aqueous extraction was usedwithout further purification (5.3 g, 76% yield).

2-Methoxy-2-(4-nitrophenyl)acetic acid was esterified according to theprocedure for the synthesis of Example 3. Purification by chromatography(15-22% EtOAc-hexanes) gave methyl 2-methoxy-2-(4-nitrophenyl)acetate asa yellow oil (2.15 g, 38% yield).

A solution of methyl 2-methoxy-2-(4-nitrophenyl)acetate (0.42 g, 1.87mmol) in absolute EtOH (15 mL) was degassed by alternately putting underhouse vacuum and argon three times for several minutes each then 10%Pd/C (0.19 g) was added. The mixture was stirred under H₂ (1 atm.) for 3hrs then diluted with EtOAc and filtered through a pad of Celite andsilica gel. The filtrate was concentrated in vacuo. Purification bychromatography (25-40% EtOAc-hexanes) provided methyl2-(4-aminophenyl)-2-methoxyacetate as a yellow oil containing impurities(0.6 g from two batches, 77% yield). The compound was used withoutfurther purification.

To a solution of methyl 2-(4-aminophenyl)-2-methoxyacetate (0.6 g, 3.07mmol) in anhydrous pyridine (6 mL) under argon was added3-chloropropane-1-sulfonyl chloride (0.5 mL, 4.11 mmol) dropwise. Theexothermic reaction was cooled briefly over a cold H₂O bath. Afterstirring for 1 hr, the reaction was diluted with H₂O, 1 M HCl and brineand extracted with EtOAc. The combined organics were washed with 1 MHCl, H₂O and brine then dried over Na₂SO₄ and concentrated in vacuo togive methyl 2-(4-(3-chloropropylsulfonamido)phenyl)-2-methoxyacetate asan orange oil (1.03 g, quant. yield). The product was used withoutfurther purification.

To a solution of methyl2-(4-(3-chloropropylsulfonamido)phenyl)-2-methoxyacetate (1.03 g, 3.07mmol) in anhydr DMF (10 mL) was added N,N-diisopropylethyl amine (2.0mL, 11.5 mmol). The mixture was heated at 50° C. under argon for 17 hrs.After cooling to room temperature, the reaction was diluted with H₂O, 1M HCl and brine then extracted with EtOAc. The combined organics werewashed with 1 M HCl, H₂O and brine the dried over Na₂SO₄ andconcentrated in vacuo. The residue was triturated with Et₂O-EtOAc. Aftersitting overnight, the solution was decanted from solids thenconcentrated in vacuo. Purification by chromatography (50-70%EtOAc-hexanes) provided methyl2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetate as animpure oil (0.69 g, 75% yield). The product was used in the nextsynthetic step without further purification.

To a solution of methyl2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetate (0.48 g,1.6 mmol) in MeOH (21 mL) was added 1 M NaOH (7 mL, 7 mmol) slowly.After stirring at room temperature for 23 hrs, the volatiles wereremoved in vacuo and the residue was dissolved in H₂O. EtOAc was addedto the aqueous solution and saturated aqueous NH₄Cl and 1 M HCl wereadded slowly until the pH ˜3. The mixture was extracted with EtOAc thenthe aqueous layer was acidified to pH 1 and extracted with EtOAc again.The combined organics were washed with H₂O and brine, dried over Na₂SO₄and concentrated in vacuo to give2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetic acid as ayellow foam (0.378 g, 82% yield). The product was used in the nextsynthetic step without further purification.

2-(4-(1,1-Dioxidoisothiazolidin-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamidewas synthesized from2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyacetic acidfollowing the procedure for the synthesis of Example 13. Purification bychromatography (0-4% EtOH-EtOAc) gave an oil that was triturated withEt₂O. The solid was dried under vacuum to give pure2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamideas a light yellow powder (0.182 g, 64% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-2-methoxyethanonewas synthesized from2-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamideand 2-(4-bromo-3,5-dimethoxyphenyl)furan following the procedure usedfor the synthesis of Example 12. Purification by chromatography(EtOAc-hexanes) provided Example 19 as a yellow solid (0.111 g, 37%yield). MS: m/z 550.1 [M+H]⁺.

Example 201-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(Quinolin-5-Yl)Ethanone

To an ice-cold solution of quinoline-5-carbaldehyde (3.5 g, 22.3 mmol)in anhydr MeOH (30 mL) and anhydr dioxane (30 mL) was added severaldrops of a solution of KOH (6.2 g, 113.4 mmol) in MeOH (30 mL).Bromoform (2.5 mL, 30 mmol) was added, then the remaining KOH/MeOHsolution was added over a period of 10 min. After stirring for 30 minthe reaction mixture was allowed to warm slowly to room temperatureovernight then concentrated to dryness. After dissolving in a minimumamount of H₂O, the residue was acidified to pH 1 with concentrated HCl.The aqueous mixture was extracted with EtOAc several times with theaddition of brine to the aqueous layer during extraction. The combinedorganics were washed with brine, dried over Na₂SO₄ and concentrated invacuo to give 2-methoxy-2-(quinolin-5-yl)acetic acid as a semisolid (2.8g, 58% yield). The product was used without further purification.

To an ice-cold solution of 2-methoxy-2-(quinolin-5-yl)acetic acid (2.8g, 12.9 mmol) in anhydrous CH₂Cl₂ (50 mL) and NMM (3.1 mL, 29 mmol)under argon was added isobutyl chloroformate (1.9 mL, 14 mmol) dropwise.After stirring over an ice bath for 40 min, N,O-dimethylhydroxylaminehydrochloride (1.63 g, 16.8 mmol) was added in three aliquots over aperiod of 15 min. The mixture was stirred for 15 min then the ice bathwas removed. After 24 hrs, saturated aqueous NaHCO₃ was added andstirred for 30 min. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂. The combined organics were washed with saturatedaqueous NaHCO₃, H₂O and brine, dried over Na₂SO₄ and concentrated invacuo. Purification by chromatography (0-100% EtOAc-hexanes) gaveN,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamide as an oil which becamecrystalline upon standing (1.8 g, 60% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)ethanonewas synthesized from N,2-dimethoxy-N-methyl-2-(quinolin-5-yl)acetamideand 2-(4-bromo-3,5-dimethoxyphenyl)furan following the procedure usedfor the synthesis of Example 12. Purification by chromatography(EtOAc-hexanes) provided1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(quinolin-5-yl)ethanoneas a light yellow foam (0.102 g, 46% yield). MS: m/z 482.1 [M+H]⁺.

Example 211-(5-(3,5-Dimethoxy-4-Methylphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

To a solution of 3,5-dimethoxy-4-methylbenzaldehyde (3.0 g, 16.8 mmol)in CH₂Cl₂ (35 mL) was added meta-chloroperoxybenzoic acid (77% purity;5.8 g, 25.9 mmol). After stirring at room temperature for 19 hrs,additional meta-chloroperoxybenzoic acid (77% purity; 3.5 g, 15.6 mmol)was added. After heating for 4 hrs at 40° C. and cooling to roomtemperature, 10% aqueous Na₂S₂O₅ was added and the mixture was stirredfor 30 min. The mixture was diluted with CH₂Cl₂ and the layersseparated. The organics were washed with 10% aqueous Na₂S₂O₅, ˜5%aqueous NaHCO₃ and brine then dried over MgSO₄ and concentrated to give3,5-dimethoxy-4-methylphenyl formate as a yellow solid (2.9 g, 88%yield).

To a solution of 3,5-dimethoxy-4-methylphenyl formate (2.9 g, 14.8 mmol)in wet MeOH (81 mL) was added K₂CO₃ (8.1 g, 58.6 mmol). The mixture wasstirred for 2 hrs at room temperature then H₂O (2-3 mL) was added. Afterstirring for 21 hrs, the mixture was diluted with H₂O, acidified with 6MHCl to pH 3-4, and extracted with EtOAc. The combined organics werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo.Purification by chromatography (0-35% EtOAc-hexanes) gave3,5-dimethoxy-4-methylphenol as an impure yellow powder (0.71 g, 29%yield).

To a suspension of 3,5-dimethoxy-4-methylphenol in anhydr CH₂Cl₂ (10 mL)under argon was added dry pyridine (0.4 mL, 4.9 mmol) then the mixturewas cooled over an ice bath. Trifluoromethanesulfonic anhydride (0.52 g,3.1 mmol) was added dropwise and the reaction was stirred for 1 hr.Saturated aqueous NaHCO₃ was added and stirred then it was warmed toroom temperature. The mixture was diluted with CH₂Cl₂ and the layerswere separated. The organics were washed with H₂O and saturated aqueousNaHCO₃ then dried over MgSO₄ and concentrated in vacuo to give3,5-dimethoxy-4-methylphenyl trifluoromethanesulfonate as a yellow oil(0.508 g, 60% yield). The product was used without further purification.

To a solution of 3,5-dimethoxy-4-methylphenyl trifluoromethanesulfonate(0.50 g, 1.67 mmol) in DME (15 mL) was added 2-furylboronic acid (0.245g, 2.2 mmol), LiCl (0.149 g, 3.5 mmol), 2 M aqueous Na₂CO₃ (1.8 mL, 3.6mmol) and tetrakis(triphenylphosphine)palladium (0.098 g, 0.085 mmol)and the mixture was degassed as described previously. The reaction washeated at 80° C. under argon for 22 hrs. After cooling to roomtemperature, the reaction was diluted with H₂O and extracted with EtOAc.The combined organics were washed with H₂O, saturated aqueous NH₄Cl, H₂Oand brine, dried over Na₂SO₄ and concentrated in vacuo. Purification bychromatography (0-25% Et₂O-hexanes) gave2-(3,5-dimethoxy-4-methylphenyl)furan as a white solid (0.28 g, 77%yield).

N,2-Dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamidewas reacted with 2-(3,5-dimethoxy-4-methylphenyl)furan according to theprocedure used for the synthesis of Example 12. Purification bychromatography (EtOAc-hexanes) gave1-(5-(3,5-dimethoxy-4-methylphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanoneas a yellow foam (0.148 g, 29% yield). MS: m/z 449.2 [M+H]⁺.

Example 221-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-(4-(5-Cyclopropyl-1,3,4-Oxadiazol-2-Yl)Phenyl)-2-Methoxyethanone

4-(((Tert-butyldimethylsilyl)oxy)methyl)benzohydrazide was reacted withethyl cyclopropanecarbimidate hydrochloride according to the procedureused for the synthesis of Example 18. Purification by chromatography(EtOAc-hexanes) gave2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-cyclopropyl-1,3,4-oxadiazoleas a brown oil (3.7 g, 40% yield).

(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)methanol was synthesizedfrom2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-cyclopropyl-1,3,4-oxadiazoleaccording to the procedure for Example 18.(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)methanol was isolated asan off-white solid and was used in the next synthetic step withoutfurther purification (2.2 g, 84% yield).

4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)benzaldehyde was synthesized from(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)methanol according to theprocedure for Example 18. Purification by chromatography (EtOAc-hexanes)gave 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)benzaldehyde as a white solid(1.8 g, 82% yield).

2,2,2-Trichloro-1-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)ethanolwas synthesized from 4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)benzaldehydeaccording to the procedure for the synthesis of Example 18. The productwas isolated as a white solid and used without further purification (2.5g, 89% yield).

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyacetic acidwas synthesized from2,2,2-trichloro-1-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)ethanolfollowing the procedure used for the synthesis of Example 18. Theproduct was isolated as a yellow semi-solid and used for the nextsynthetic step without further purification (1.8 g, 90% yield).

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamidewas synthesized from2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyacetic acidaccording to the procedure for the synthesis of Example 18. The productwas isolated as a white semi-solid (0.56 g, 27% yield).

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamidewas reacted with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to theprocedure for the synthesis of Example 12. Purification bychromatography (EtOAc-hexanes) gave1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanoneas a yellow foam (0.126 g, 31% yield). MS: m/z 539.2 [M+H]⁺.

Example 231-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(6-(Piperidin-1-Yl)Pyridin-3-Yl)Ethanone

2-Methoxy-2-(6-(piperidin-1-yl)pyridin-3-yl)acetic acid was synthesizedfrom 6-(piperidin-1-yl)nicotinaldehyde according to the procedure usedfor the synthesis of Example 1 except that the reaction mixture wascooled over ice before the addition of KOH-MeOH solution. The productwas isolated as a light beige foam and was used without furtherpurification (0.569 g, 52% yield).

N,2-Dimethoxy-N-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)acetamide wassynthesized from 2-methoxy-2-(6-(piperidin-1-yl)pyridin-3-yl)acetic acidaccording to the procedure used for the synthesis of Example 13.Purification by chromatography (50-100% EtOAc-hexanes) gave the productas an orange oil (0.295 g, 46% yield).

N,2-Dimethoxy-N-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)acetamide wasreacted with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to theprocedure used for Example 12. Purification by chromatography (20-75%EtOAc-hexanes) gave1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-(piperidin-1-yl)pyridin-3-yl)ethanoneas a light yellow solid (0.328 g, 65% yield). MS: m/z 515.4 [M+H]⁺.

Example 242,6-Dimethoxy-4-(5-(2-Methoxy-2-(4-Morpholinophenyl)Acetyl)Furan-2-Yl)PhenylBenzoate

4-Bromo-2,6-dimethoxyphenol (Lee, H.; et al. Tetrahedron Letters, 2004,45, 1019) was coupled with 2-furylboronic acid according to theprocedure used in the synthesis of Example 21. Purification bychromatography (20-40% EtOAc-hexanes) gave4-(furan-2-yl)-2,6-dimethoxyphenol as a light orange solid (1.95 g, 79%yield).

To a solution of 4-(furan-2-yl)-2,6-dimethoxyphenol (1.3 g, 5.9 mmol) inanhydr CH₂Cl₂ (20 mL) under argon was added Et₃N (1.6 mL, 11.5 mmol)then the mixture was cooled over an ice bath. Benzoyl chloride (0.75 mL,6.4 mmol) was added dropwise and the reaction was stirred for 3 hrs. 10%aqueous NaHCO₃ and CH₂Cl₂ were added, stirred, and the layers wereseparated. The organics were washed with H₂O and saturated aqueousNaHCO₃, dried over MgSO₄ and concentrated in vacuo. Purification bychromatography (0-25% EtOAc-hexanes) gave4-(furan-2-yl)-2,6-dimethoxyphenyl benzoate as a light yellow solid(0.54 g isolated from chromatography of approximately half of the crudeproduct; 57% yield).

4-(Furan-2-yl)-2,6-dimethoxyphenyl benzoate was reacted withN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to theprocedure described for the synthesis of Example 12 except that thereaction was warmed to only 0° C. Purification by chromatography(EtOAc-hexanes) provided2,6-dimethoxy-4-(5-(2-methoxy-2-(4-morpholinophenyl)acetyl)furan-2-yl)phenylbenzoate as a yellow solid (0.257 g, 50% yield). MS: m/z 558.2 [M+H]⁺.

Example 251-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(1-Methyl-1H-Benzo[D][1,2,3]Triazol-5-Yl)Ethanone

2-Methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetic acid wassynthesized from 1-methyl-1H-benzo[d][1,2,3]triazole-5-carbaldehydeaccording to the procedure for the synthesis of Example 23. The productwas isolated as a yellow solid (1.5 g, 96% yield).

N,2-Dimethoxy-N-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetamidewas synthesized from2-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetic acidaccording to the method used for the synthesis of Example 13.Purification by chromatography (60-100% EtOAc-hexanes) gaveN,2-dimethoxy-N-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetamideas a yellow solid (1.02 g, 57% yield).

N,2-Dimethoxy-N-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetamidewas coupled with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to theprocedure for the synthesis of Example 13. Purification bychromatography provided1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)ethanoneas a light yellow foam (0.153 g, 34% yield). MS: m/z 486.1 [M+H]⁺.

Example 261-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(Morpholinomethyl)Phenyl)Ethanone

2-Methoxy-2-(4-(morpholinomethyl)phenyl)acetic acid was synthesized from4-(morpholinomethyl)benzaldehyde following the procedure for thesynthesis of Example 23. Following the reaction, the volatiles wereremoved in vacuo. The residue was redissolved in a minimum amount of H₂Oand acidified with 1 M HCl to pH 3. The aqueous layer was concentratedin vacuo and the residue was suspended in MeOH and sonicated and warmedslightly. The mixture was filtered through Celite and concentrated invacuo to give a white solid (3 g, quant. yield). The product was takenon to the next synthetic step without purification.

N,2-Dimethoxy-N-methyl-2-(4-(morpholinomethyl)phenyl)acetamide wassynthesized from 2-methoxy-2-(4-(morpholinomethyl)phenyl)acetic acidfollowing the procedure used for Example 13. Purification bychromatography (0-7% NH₃-MeOH solution in CH₂Cl₂; 0.7 M NH₃-MeOH) gaveN,2-dimethoxy-N-methyl-2-(4-(morpholinomethyl)phenyl)acetamide as anorange oil (0.743 g, 41% yield).

N,2-Dimethoxy-N-methyl-2-(4-(morpholinomethyl)phenyl)acetamide wascoupled with 2-(4-bromo-3,5-dimethoxyphenyl)furan following theprocedure of Example 12. Purification by chromatography (0-9% NH₃-MeOHin CH₂Cl₂; 0.7 M NH₃-MeOH used) gave a mixture which was digested withEtOAc at 30-40° C. After cooling to room temperature, the crystals werecollected on a Buchner, rinsed with EtOAc and dried in vacuo to give1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(morpholinomethyl)phenyl)ethanoneas a white solid. A second batch was also isolated (0.125 g for twobatches, 13% yield). MS: m/z 530.1 [M+H]⁺.

Example 271-(5-(3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

1-Bromo-3,5-dimethoxybenzene was coupled with 2-furylboronic acidfollowing the procedure for Example 21. 2-(3,5-Dimethoxyphenyl)furan wasisolated as a colorless liquid (0.746 g, 79% yield).

N,2-Dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide was coupled with2-(3,5-dimethoxyphenyl)furan following the procedure of Example 12.1-(5-(3,5-Dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanonewas isolated as a yellow oily foam (0.343 g, 62% yield). MS: m/z 438.2[M+H]⁺.

Example 281-(5-(4-(Difluoromethoxy)-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was synthesized from4-bromo-2,6-dimethoxyphenol according to the procedure of Zafrani, Y.Tetrahedron 2009, 65, 5278 as follows. To a solution of4-bromo-2,6-dimethoxyphenol (1.08 g, 4.6 mmol) in MeCN (27 mL) was addeda solution of KOH (5.0 g, 89 mmol) in H₂O (27 mL). The mixture wasimmediately cooled over a −78° C. bath and diethyl(bromodifluoromethyl)phosphonate (1.6 mL, 8.9 mmol) was added. The flaskwas sealed with a septum and the cold bath was removed. The mixture wasstirred for a total of 3.5 hrs during which time the septum was ejectedfrom the flask. The reaction was diluted with EtOAc and the layers wereseparated. The aqueous layer was extracted with EtOAc and the combinedorganics were washed with 1 M NaOH, H₂O and brine then dried over Na₂SO₄and concentrated in vacuo. Purification by chromatography (0-30%EtOAc-hexanes) provided 5-bromo-2-(difluoromethoxy)-1,3-dimethoxybenzeneas a white solid (0.808 g, 62% yield).

5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was coupled with2-furylboronic acid following the procedure for the synthesis of Example21. Purification by chromatography (0-30% EtOAc-hexanes) provided2-(4-(difluoromethoxy)-3,5-dimethoxyphenyl)furan as a white crystallinematerial (0.555 g, 67% yield).

2-(4-(Difluoromethoxy)-3,5-dimethoxyphenyl)furan was coupled withN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide following theprocedure used for the synthesis of Example 12. Purification bychromatography (EtOAc-hexanes) provided1-(5-(4-(difluoromethoxy)-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)-ethanoneas a brown oil (0.021 g, 6% yield). MS: m/z 504.2 [M+H]⁺.

Example 291-(5-(4-Ethoxy-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

To a suspension of 4-(furan-2-yl)-2,6-dimethoxyphenol (0.493 g, 2.24mmol) in anhydr DMF (10 mL) under argon was added Cs₂CO₃ (1.2 g, 3.7mmol) and iodoethane (0.22 mL, 2.7 mmol). The mixture was stirred for 20min then heated at 80° C. for 2 hrs. After cooling to room temperature,the reaction was diluted with H₂O and EtOAc then it was acidified withthe addition of 6 M HCl. The layers were separated and the aqueous layerwas extracted with EtOAc. The combined organics were diluted withhexanes and washed with H₂O and brine, dried over Na₂SO₄ and filteredthrough a pad of silica gel on Celite. The filtrate was concentrated invacuo to give 2-(4-ethoxy-3,5-dimethoxyphenyl)furan as a beige solid(0.513 g, 92% yield). The product was used without further purification.

2-(4-Ethoxy-3,5-dimethoxyphenyl)furan was coupled withN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to theprocedure for the synthesis of Example 12. Purification bychromatography (EtOAc-hexanes) gave1-(5-(4-ethoxy-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanoneas a yellow foam (0.263 g, 58% yield). MS: m/z 482.2 [M+H]⁺.

Example 302-(4-(2H-1,2,3-Triazol-2-Yl)Phenyl)-1-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxyethanone

To a solution of 4-(2H-1,2,3-triazol-2-yl)benzaldehyde (1.0 g, 5.77mmol) in anhydr MeOH (15 mL) at 0° C. (bath temperature) was addedbromoform (1.82 g, 7.21 mmol) with stirring. Solid KOH (1.62 g, 28.9mmol) was added in aliquots over a period of 10 min. The mixture wasstirred for 1 hour and the cold bath was removed. After stirring for 30min, the reaction was allowed to warm slowly to room temperatureovernight then concentrated to dryness. After dissolving in a minimumamount of H₂O, the residue was acidified to pH 1 with 6 M HCl. Theaqueous mixture was extracted with EtOAc several times with the additionof brine to the aqueous layer during extraction. The combined organicswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-methoxyacetic acid as an oil(1.19 g, 88% yield). The product was used without further purification.

To a solution of 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-2-methoxyaceticacid (1.19 g, 5.1 mmol in anhydr CH₂Cl₂ (15 ml) was added4-methylmorpholine (1.55 g, 15.3 mmol) and it was cooled over an icebath. Isobutylchloroformate (0.84 g, 6.12 mmol) was added and stirredfor 45 min. N,O-Dimethylhydroxylamine HCl (0.746 g, 7.65 mmol) was addedand the mixture was allowed to stir overnight while warming to roomtemp. Saturated aqueous NaHCO₃ (15 ml) was added and stirred for 5 min.The organic layer was dried over Na₂SO₄ and evaporated to dryness.Purification by chromatography (100% EtOAc) gave2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide as awhite solid (0.63 g, 44% yield).

To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.20 g, 0.71mmol) in anhydr THF (10 mL) under argon in an oven-dried flask cooled to−78° C. was added lithium diisopropylamide (2.0 M inTHF/heptane/ethylbenzene; 0.43 mL, 0.85 mmol) dropwise. After stirringfor 1 hr at −78° C., a solution of2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide(0.195 g, 0.71 mmol) in THF (2 mL) was added dropwise. After stirringfor 25 min, the mixture was allowed to warm to room temp while stirringfor 2 hrs. The reaction was quenched with the addition of saturatedaqueous NH₄Cl and EtOAc was added. The layers were separated and theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. Purification by chromatography (30% EtOAc-hexanes) provided2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanoneas a yellow solid (0.07 g, 10% yield). MS: m/z 497.9 [M+H]⁺.

Example 312-(4-(1H-1,2,3-Triazol-1-Yl)Phenyl)-1-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxyethanone

2-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-2-methoxyacetic acid was preparedfrom 4-(1H-1,2,3-triazol-1-yl)benzaldehyde according to the procedureused in Example 30. The product was obtained as an oil and used withoutfurther purification (1.02 g, 76% yield).

2-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide wasprepared from 2-(4-(1H-1,2,3-triazol-1-yl)phenyl)-2-methoxyacetic acidaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc/hexanes) gave of the product as an oil (0.73g, 58% yield).

2-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and2-(4-(1H-1,2,3-triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamideaccording to the procedure used in Example 30. Purification bychromatography (50% EtOAc/hexanes) gave2-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanoneas a yellow solid (0.025 g, 7% yield). MS: m/z 498.2 [M+H]⁺.

Example 322-(4-(1H-1,2,4-Triazol-1-Yl)Phenyl)-1-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxyethanone

2-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-2-methoxyacetic acid was preparedfrom 4-(1H-1,2,4-triazol-1-yl)benzaldehyde according to the procedureused in Example 30. The crude product was obtained as a white solid andused without further purification (1.9 g, 47% yield).

2-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide wasprepared from 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2-methoxyacetic acidaccording to the procedure used in Example 30. Purification bychromatography (100% EtOAc) gave the product as an off-white solid (0.30g, 26% yield).

2-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc-hexanes) followed by another purification (40%acetone-hexanes) gave2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanoneas a pale yellow solid (0.078 g, 11% yield). MS: m/z 498.2 [M+H]⁺.

Example 331-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(2-Methyl-2H-Tetrazol-5-Yl)Phenyl)Ethanone

2-Methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetic acid wasprepared from 4-(2-methyl-2H-tetrazol-5-yl)benzaldehyde according to theprocedure used in Example 30. The crude product was obtained as an oiland used without further purification (0.88 g, 86% yield).

To a solution of 2-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)aceticacid (0.87 g, 3.5 mmol) in anhydr CH₂Cl₂ (10 ml) was addedN,N-diisopropylethylamine (1.36 g, 10.5 mmol) while cooling over an icebath. bis(2-Methoxyethyl)aminosulfur trifluoride (0.93 g, 4.2 mmol) wasadded and stirred 15 min. N,O-Dimethylhydroxylamine HCl (0.512 g, 5.25mmol) was added and the mixture was allowed to stir overnight whilewarming to room temp. Saturated aqueous NaHCO₃ (15 ml) was added andstirred for 5 min. The organic layer was dried over Na₂SO₄ andevaporated to dryness. Purification by chromatography (60%EtOAc-hexanes) gaveN,2-dimethoxy-N-methyl-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetamideas a clear oil (0.425 g, 42% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (40% EtOAc/hexanes) gave the product as a pale yellowsolid (0.106 g, 29% yield). MS: m/z 513.3 [M+H]⁺.

Example 341-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Thiadiazol-2-Yl)Phenyl)Ethanone

To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (2.0 g, 11.17 mmol)in dioxane (40 ml) was added 4-formylbenzeneboronic acid (3.35 g, 22.34mmol) and 2M Na₂CO₃ (23 ml). This mixture was degassed with a stream ofargon for 2 min. Tetrakis(triphenylphosphine)palladium (0.636 g, 0.55mmol) was added and this mixture was heated at reflux overnight underargon. After cooling to room temperature, H₂O (30 ml) and EtOAc (50 ml)were added and stirred for 5 min. The organic layer was separated andwashed with brine, dried over Na₂SO₄ and concentrated in vacuo.Purification by chromatography (10 to 20% EtOAc/hexanes) gave4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde as a pale yellow liquid(1.16 g, 51% yield).

2-Methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetic acid wasprepared from 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde accordingto the procedure used in Example 30. The crude product was obtained asan oil and used without further purification (1.12 g, 75% yield).

N,2-Dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetamidewas prepared from2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetic acidaccording to the procedure used in Example 33. Purification bychromatography (100% EtOAc) gave the product as a pale yellow oil (0.177g, 26% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (70% EtOAc/hexanes) gave the product as a pale yellowsolid (0.044 g, 15% yield). MS: m/z 529.3 [M+H]⁺.

Example 351-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(2-Methylthiazol-4-Yl)Phenyl)Ethanone

2-Methoxy-2-(4-(2-methylthiazol-4-yl)phenyl)acetic acid was preparedfrom 4-(2-methylthiazol-4-yl)benzaldehyde according to the procedureused in Example 30. The crude product was obtained as an oil and usedwithout further purification (0.972 g, 78% yield).

N,2-Dimethoxy-N-methyl-2-(4-(2-methylthiazol-4-yl)phenyl)acetamide wasprepared from 2-methoxy-2-(4-(2-methylthiazol-4-yl)phenyl)acetic acidaccording to the procedure used in Example 33. Purification bychromatography (70% EtOAc/hexanes) gave the product as an oil (0.516 g,46% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(2-methylthiazol-4-yl)phenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(2-methylthiazol-4-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc/hexanes) gave the product as a off white solid(0.039 g, 10% yield). MS: m/z 528.2 [M+H]⁺.

Example 362-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)-1-(5-(3,4,5-Trimethoxyphenyl)Furan-2-Yl)Ethanone

2-(3,4,5-Trimethoxyphenyl)furan was prepared from5-iodo-1,2,3-trimethoxybenzene according to the procedure used inExample 12. Purification by chromatography (10% EtOAc/hexanes) gave theproduct as an off white solid (1.2 g, 60% yield).

To a solution of 2-(3,4,5-trimethoxyphenyl)furan (1.4 g, 5.98 mmol) inanhydr THF (70 mL) under argon in an oven-dried flask cooled to −78° C.was added n-butyl lithium (2.5 M in hexanes; 2.63 mL, 6.28 mmol)dropwise. After stirring for 1 hr at −78° C., a solution ofN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide(1.75 g, 6.0 mmol) in THF (5 mL) was added dropwise. After stirring for25 min, the mixture was allowed to warm to room temp while stirring for2 hrs. The reaction was quenched with the addition of saturated aqueousNH₄Cl then brine and EtOAc were added. The layers were separated and theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. Purification by column chromatography (60% EtOAc-hexanes) gave2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanoneas a fluffy yellow solid (0.81 g, 29% yield). MS: m/z 465.3 [M+H]⁺.

Example 371-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(Pyridin-3-Yl)Phenyl)Ethanone

2-Methoxy-2-(4-(pyridin-3-yl)phenyl)acetic acid was prepared from4-(pyridin-3-yl)benzaldehyde according to the procedure used in Example30 except pH 4 was used during the extractive work-up. The crude productwas obtained as an oil and used without further purification (0.415 g,33% yield).

N,2-Dimethoxy-N-methyl-2-(4-(pyridin-3-yl)phenyl)acetamide was preparedfrom 2-methoxy-2-(4-(pyridin-3-yl)phenyl)acetic acid according to theprocedure used in Example 33. Purification by chromatography (100%EtOAc) gave the product as an oil (0.232 g, 48% yield.

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyridin-3-yl)phenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(pyridin-3-yl)phenyl)acetamide according tothe procedure used in Example 30. Purification by chromatography (50%EtOAc/hexanes) gave the product as an off white solid (0.126 g, 35%yield). MS: m/z 508.2 [M+H]⁺.

Example 381-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Ethoxy-2-(4-Morpholinophenyl)Ethanone

2-Ethoxy-2-(4-morpholinophenyl)acetic acid was synthesized from4-morpholinobenzaldehyde according to the procedure used for thesynthesis of Example 1 except that EtOH was used as the solvent. Theproduct was isolated as a pale red oil and used without furtherpurification.

2-Ethoxy-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide wassynthesized from 2-ethoxy-2-(4-morpholinophenyl)acetic acid followingthe procedure used for Example 13. Purification by chromatography(EtOAc-hexanes) provided the product as a yellow solid (1.0 g, 31% yieldfor two steps).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-morpholinophenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and2-ethoxy-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide according tothe procedure used in Example 30. Purification by chromatography (50%EtOAc/hexanes) gave the product as a yellow solid (0.129 g, 34% yield).MS: m/z 530.2 [M+H]⁺.

Example 391-(5-(3-Bromo-4,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

3-Bromo-4,5-dimethoxyphenol was prepared from3-bromo-4,5-dimethoxybenzaldehyde according to the procedure used inExample 21. Crystallization from ether/hexanes gave the product as awhite solid (2.02 g, 39% yield).

3-Bromo-4,5-dimethoxyphenyl trifluoromethanesulfonate was prepared from3-bromo-4,5-dimethoxyphenol according to the procedure used in Example21. Evaporation to dryness gave the product as a pale yellow oil (3.3 g,100% yield).

2-(3-Bromo-4,5-dimethoxyphenyl)furan was prepared from3-bromo-4,5-dimethoxyphenyl trifluoromethanesulfonate according to theprocedure used in Example 21. Purification by chromatography (10%ether/hexanes) gave the product as a pale yellow oil (1.7 g, 73% yield).

1-(5-(3-Bromo-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas prepared from 2-(3-bromo-4,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (70% EtOAc/hexanes) gave the product as a pale yellowsolid (0.037 g, 10% yield). MS: m/z 513.1 [M+H]⁺.

Example 401-(5-(3-Chloro-4,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

3-Chloro-4,5-dimethoxyphenol was synthesized from3-chloro-4,5-dimethoxybenzaldehyde according to the procedure used forthe synthesis of Example 21. The crude solid obtained was digested with˜10% EtOAc-hexanes at 40° C. for 1 hr. After cooling to roomtemperature, the solid was collected on a Buchner and dried in vacuo togive a crystalline beige solid (1.44 g, 38% yield for two steps).

3-Chloro-4,5-dimethoxyphenyl trifluoromethanesulfonate was synthesizedfrom 3-chloro-4,5-dimethoxyphenol according to the procedure for thesynthesis of Example 21. The product was isolated as a pale yellowliquid and used in the next synthetic step without further purification(2.33 g, 96% yield).

2-(3-Chloro-4,5-dimethoxyphenyl)furan was synthesized from3-chloro-4,5-dimethoxyphenyl trifluoromethanesulfonate according to theprocedure used in the synthesis of Example 21. Purification bychromatography (10% Et₂O-hexanes) gave the product as a pale yellow oil(1.6 g, 94% yield).

1-(5-(3-Chloro-4,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas prepared from 2-(3-chloro-4,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (70% EtOAc/hexanes) gave the product as a pale yellowsolid (0.051 g, 12% yield). MS: m/z 469.2 [M+H]⁺.

Example 411-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-(Cyclopropylmethoxy)-2-(4-Morpholinophenyl)Ethanone

To a solution of 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde (5.3 g,27.7 mmol) in cyclopropylmethanol (25 mL) and anhydrous dioxane (25 mL)at 0° C. (bath temperature) was added several drops of a solution of KOH(7.77 g, 138.5 mmol) in cyclopropylmethanol (35 mL). Bromoform (3.1 mL,35.2 mmol) was added, then the remaining KOH/cyclopropylmethanolsolution was added over a period of 20 min. After stirring for 30 min,the reaction mixture was allowed to warm slowly to room temperatureovernight then concentrated to dryness. After dissolving in a minimumamount of H₂O, the residue was acidified to pH 1 with concentrated HCl.The aqueous mixture was extracted with EtOAc several times with theaddition of brine to the aqueous layer during extraction. The combinedorganics were washed with brine, dried over Na₂SO₄ and concentrated invacuo to give2-(cyclopropylmethoxy)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)aceticacid as a semisolid which was then recrystallized from Et₂O (0.5 g, 7%yield).

2-(Cyclopropylmethoxy)-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamidewas synthesized from2-(cyclopropylmethoxy)-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)aceticacid according to the procedure used in the synthesis of Example 13.Purification by chromatography (0-70% EtOAc-hexanes) gave the product asan oil (0.48 g, 77% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(cyclopropylmethoxy)-2-(4-morpholinophenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and2-(cyclopropylmethoxy)-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (40% EtOAc/hexanes) gave the product as a pale yellowsolid (0.092 g, 23% yield). MS: m/z 556.3 [M+H]⁺.

Example 421-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(6-Methoxypyridin-3-Yl)Ethanone

2-Methoxy-2-(6-methoxypyridin-3-yl)acetic acid was prepared from6-methoxynicotinaldehyde according to the procedure used in Example 37.The crude product was obtained as an oil and used without furtherpurification (5.67 g, 79% yield).

N,2-Dimethoxy-2-(6-methoxypyridin-3-yl)-N-methylacetamide was preparedfrom 2-methoxy-2-(6-methoxypyridin-3-yl)acetic acid according to theprocedure used in Example 33. Purification by chromatography (60%EtOAc/hexanes) gave the product as an oil (0.97 g, 40% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-methoxypyridin-3-yl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-2-(6-methoxypyridin-3-yl)-N-methylacetamide according tothe procedure used in Example 30. Purification by chromatography (50%EtOAc/hexanes) gave the product as a pale yellow solid (0.092 g, 28%yield). MS: m/z 462.2 [M+H]⁺.

Example 431-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-(4-((Dimethylamino)Methyl)Phenyl)-2-Methoxyethanone

2-(4-((Dimethylamino)methyl)phenyl)-2-methoxyacetic acid was preparedfrom 4-((dimethylamino)methyl)benzaldehyde according to the procedureused in Example 37. After the pH was adjusted to 4 the aqueous solutionwas evaporated to dryness. MeOH (20 ml) was added with swirling and thematerial was filtered. Evaporation to dryness gave the crude productthat was used without further purification (1.3 g, 95% yield).

2-(4-((Dimethylamino)methyl)phenyl)-N,2-dimethoxy-N-methylacetamide wasprepared from 2-(4-((dimethylamino)methyl)phenyl)-2-methoxyacetic acidaccording to the procedure used in Example 33. Purification bychromatography (100% EtOAc) gave the product as an oil (0.212 g, 14%yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-((dimethylamino)methyl)phenyl)-2-methoxyethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and2-(4-((dimethylamino)methyl)phenyl)-N,2-dimethoxy-N-methylacetamideaccording to the procedure used in Example 30. Purification bychromatography (4% MeOH/CH₂Cl₂) gave the product as a pale yellow oil(0.004 g, 1% yield). MS: m/z 488.3 [M+H]⁺.

Example 441-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(6-Morpholinopyridin-3-Yl)Ethanone

2-Methoxy-2-(6-morpholinopyridin-3-yl)acetic acid was prepared from6-morpholinonicotinaldehyde according to the procedure used in Example30 except the aqueous mixture was adjusted to pH 4 during the extractivework-up. The crude product was obtained as an oil and used withoutfurther purification (1.17 g, 89% yield).

N,2-Dimethoxy-N-methyl-2-(6-morpholinopyridin-3-yl)acetamide wasprepared from 2-methoxy-2-(6-morpholinopyridin-3-yl)acetic acidaccording to the procedure used in Example 33. Purification bychromatography (80% EtOAc/hexanes) gave the product as an oil (0.692 g,51% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-morpholinopyridin-3-yl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(6-morpholinopyridin-3-yl)acetamide accordingto the procedure used in Example 30. Purification by chromatography (60%EtOAc/hexanes) gave the product as a pale yellow solid (0.04 g, 11%yield). MS: m/z 517.3 [M+H]⁺.

Example 451-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(Pyrazin-2-Yl)Phenyl)Ethanone

2-Methoxy-2-(4-(pyrazin-2-yl)phenyl)acetic acid was prepared from4-(pyrazin-2-yl)benzaldehyde according to the procedure used in Example30 except the aqueous mixture was adjusted to pH 4 during the extractivework-up. The crude product was obtained as an oil and was used withoutfurther purification (1.21 g, 91% yield).

N,2-Dimethoxy-N-methyl-2-(4-(pyrazin-2-yl)phenyl)acetamide was preparedfrom 2-methoxy-2-(4-(pyrazin-2-yl)phenyl)acetic acid according to theprocedure used in Example 33. Purification by chromatography (80%EtOAc/hexanes) gave the product as an oil (0.493 g, 35% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyrazin-2-yl)phenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(pyrazin-2-yl)phenyl)acetamide according tothe procedure used in Example 30. Purification by chromatography (60%EtOAc/hexanes) gave the product as a pale yellow solid (0.060 g, 17%yield). MS: m/z 509.3 [M+H]⁺.

Example 462-Ethoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)-1-(5-(3,4,5-Trimethoxyphenyl)Furan-2-Yl)Ethanone

2-Ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acid wassynthesized from 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzaldehyde followingthe procedure for Example 47. The product was isolated as a semisolidand used without further purification (2.6 g, 93% yield).

2-Ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamidewas synthesized from2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetic acidaccording to the procedure for the synthesis of Example 41. Purificationby chromatography of (0-60% EtOAc-hexanes) gave the product as an oil(1.0 g, 30% yield).

2-Ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone was prepared from 2-(3,4,5-trimethoxyphenyl)furanand2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc/hexanes) gave the product as a pale yellowsolid (0.060 g, 15% yield). MS: m/z 479.4 [M+H]⁺.

Example 471-(5-(4-Bromo-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Ethoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc/hexanes) gave the product as a pale yellowsolid (0.070 g, 19% yield). MS: m/z 527.3 [M+H]⁺.

Example 481-(5-(4-Fluoro-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

2-(4-Fluoro-3,5-dimethoxyphenyl)furan was prepared from5-bromo-2-fluoro-1,3-dimethoxybenzene (U.S. Pat. No. 6,177,154 B1)according to the procedure used in Example 15. Purification bychromatography (10% EtOAc/hexanes) gave the product as a white solid(2.1 g, 58% yield).

1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanonewas prepared from 2-(4-fluoro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to theprocedure used in Example 30. Purification by chromatography (60%EtOAc/hexanes) gave the product as a pale yellow solid (0.072 g, 16%yield). MS: m/z 456.4 [M+H]⁺.

Example 491-(5-(4-Chloro-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Thiadiazol-2-Yl)Phenyl)Ethanone

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanonewas prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (80% EtOAc-hexanes) gave the product as a pale yellowsolid (0.106 g, 26% yield). MS: m/z 485.4 [M+H]⁺.

Example 501-(5-(4-Chloro-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

2-(4-Chloro-3,5-dimethoxyphenyl)furan was prepared from5-bromo-2-chloro-1,3-dimethoxybenzene (EP1568691 A1) according to theprocedure used in Example 15. Purification by chromatography (10%ether/hexanes) gave the product as a white solid (1.24 g, 75% yield).

1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanonewas prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to theprocedure used in Example 30. Purification by chromatography (70%EtOAc/hexanes) gave the product as a pale yellow solid (0.201 g, 43%yield). MS: m/z 472.2 [M+H]⁺.

Example 511-(3-(3,4-Dimethoxyphenyl)-1H-Pyrazol-1-Yl)-2-(4-Fluorophenyl)-2-Methoxyethanone

To a solution of 2-(4-fluorophenyl)-2-methoxyacetic acid (0.11 g, 0.61mmol) in anhydrous THF (2 mL) at room temperature was added DCC (0.14 g,0.67 mmol) in one portion. After stirring for 10 min,3-(3,4-dimethoxyphenyl)-1H-pyrazole (0.14 g, 0.67 mmol) was added in oneportion. After 48 hrs, the reaction mixture was diluted with EtOAc andthe solids removed via filtration. The filtrate was concentrated invacuo. Purification by chromatography (0-30% EtOAc-hexanes) gave theproduct as an oil (0.12 g, 46% yield). MS: m/z 371.1 [M+H]⁺.

Example 521-(3-(4-Bromo-3,5-Dimethoxyphenyl)-1H-Pyrazol-1-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

1-(3-(4-Bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl)ethanonewas synthesized from 3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazole(prepared according to Journal of Org. Chem., 2003, 68, 5381) and2-methoxy-2-(4-morpholinophenyl)acetic acid using the analogousprocedure as for Example 51 to give1-(3-(4-bromo-3,5-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a solid (0.065 g, 22% yield). MS: m/z 516.1 [M+H]⁺.

Example 531-(3-(3,4-Dimethoxyphenyl)-1H-Pyrazol-1-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

To a solution of 2-methoxy-2-(4-morpholinophenyl)acetic acid (0.1 g,0.42 mmol) and 3-(3,4-dimethoxyphenyl)-1H-pyrazole (0.86 g, 0.42 mmol)in anhydrous DMF (4 mL) at room temperature was addeddiisopropylethylamine (0.22 ml, 1.26 mmol) thenbromotripyrrolidinophosphonium hexafluorophosphate (0.23 g, 0.50 mmol).After 24 hrs, saturated aqueous NaHCO₃ was added. The layers wereseparated and the aqueous layer was extracted with EtOAc. The combinedorganics were washed with H₂O and brine, dried over Na₂SO₄ andconcentrated in vacuo. Purification by chromatography (0-60%EtOAc-hexanes) gave1-(3-(3,4-dimethoxyphenyl)-1H-pyrazol-1-yl)-2-methoxy-2-(4-morpholinophenyl)ethanoneas a white solid (0.90 g, 50% yield). MS: m/z 438.2 [M+H]⁺.

Example 541-(5-(4-Bromo-3,5-Dimethoxyphenyl)-1,2,4-Oxadiazol-3-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

To a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide(1.5 g, 5.1 mmol) in anhydr CH₂Cl₂ (12 mL) and anhydr toluene (6 mL) at−78° C. was added a solution of DIBALH (1 M in hexanes, 7.8 mL, 7.8mmol) dropwise over 5 min. After stirring at −78° C. for 1 hr, thereaction was quenched with the dropwise addition of EtOAc. The mixturewas stirred 2 min then Et₂O and saturated aqueous NH₄Cl were added andthe mixture was warmed to room temp. After stirring for 30 min themixture was diluted with EtOAc and H₂O and the layers separated. 10%Aqueous potassium sodium tartrate was added to the aqueous layer and itwas extracted with EtOAc/Et₂O. The combined organics were washed withsaturated aqeuous NH₄Cl and dried over Na₂SO₄ to give2-methoxy-2-(4-morpholinophenyl)acetaldehyde as a yellow oil (1.27 g).The product was used in the next synthetic step without furtherpurification.

To a solution of 2-methoxy-2-(4-morpholinophenyl)acetaldehyde (1.27 g,˜5.1 mmol) in Et₂O (35 mL) under a drying tube was added trimethylsilylcyanide (1 mL, 8 mmol) and ZnI₂ (50 mg, 0.16 mmol). After stirring atroom temperature for 15.5 hrs, saturated aqueous NaHCO₃ was added andthe mixture was stirred several hrs. The mixture was diluted with EtOAcand H₂O and the layers were separated. The organic layers were washedwith saturated aqueous NaHCO₃, dried over Na₂SO₄ and concentrated invacuo to give 2-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanenitrileas an orange foam (1.26 g). The product was used without furtherpurification.

To a solution of2-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanenitrile (˜5.1 mmol) inanhydr CH₂Cl₂ (17 mL) under argon was added pyridiniumpara-toluenesulfonate (0.094 g, 0.37 mmol) and ethyl vinyl ether (17 mL,178 mmol). The mixture was placed under a drying tube and stirred atroom temperature for 16 hrs. Additional ethylvinyl ether (4 mL, 42 mmol)and pyridinium para-toluenesulfonate (0.11 g, 0.44 mmol) were added andthe mixture stirred for 24 hrs more. Saturated aqueous NaHCO₃ was addedto the mixture then it was diluted with H₂O and CH₂Cl₂. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂. The combinedorganics were washed with brine, dried over MgSO₄ and concentrated invacuo. Purification by chromatography (20-35% EtOAc-hexanes containing1% Et₃N) gave2-(1-ethoxyethoxy)-3-methoxy-3-(4-morpholinophenyl)propanenitrile (0.606g, 35% for three steps).

To a solution of2-(1-ethoxyethoxy)-3-methoxy-3-(4-morpholinophenyl)propanenitrile (0.60g, 1.8 mmol) in anhydr MeOH (10 mL) under argon was added NH₂OH.HCl(0.175 g, 2.5 mmol) and NaHCO₃ (0.234 g, 2.8 mmol). The reaction washeated briefly at 75° C. then at 60° C. for 16 hrs. After cooling toroom temp, the mixture was concentrated in vacuo to give(Z)-2-(1-ethoxyethoxy)-N′-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanimidamidewhich was used in the next synthetic step without further purification(0.777 g).

To an ice-cold suspension of(Z)-2-(1-ethoxyethoxy)-N-hydroxy-3-methoxy-3-(4-morpholinophenyl)propanimidamide(˜1.41 mmol) in anhydr CH₂Cl₂ under argon was added Et₃N (0.8 mL, 5.7mmol), 4-bromo-3,5-dimethoxybenzoyl chloride (0.434 g, 1.6 mmol) and4-dimethylaminopyridine (0.015 g, 0.12 mmol). The reaction was stirredfor 1 hr over an ice bath then allowed to warm to room temperature.After stirring for 3 hrs at room temp, additional4-bromo-3,5-dimethoxybenzoyl chloride (0.047 g, 0.17 mmol) was added andthe mixture was stirred for an additional hour. 10% Aqueous NaHCO₃solution was added and stirred for 20 min. The layers were separated andthe organic layer was washed with H₂O, brine, dried over MgSO₄ andconcentrated in vacuo to give an off-white foam.

This synthetic intermediate was dissolved in anhydr DMF (15 mL) underargon then heated at 120° C. for 7 hrs. After cooling to room temp, thereaction was diluted with H₂O and extracted with EtOAc. The combinedorganics were washed with H₂O and brine, dried over Na₂SO₄ andconcentrated in vacuo. Purification by chromatography (25-35%EtOAc-hexanes containing 1% Et₃N) gave4-(4-(2-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-(1-ethoxyethoxy)-1-methoxyethyl)phenyl)morpholineas a light yellow oil (0.335 g, 40% yield).

To a solution of4-(4-(2-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-(1-ethoxyethoxy)-1-methoxyethyl)phenyl)morpholine(0.335 g, 0.57 mmol) in MeOH (15 mL) was added pyridiniumpara-toluenesulfonate (0.15 g, 0.6 mmol) and the mixture was stirred atroom temperature for 16.5 hrs. The reaction was then heated at 40° C.for 6 hrs, cooled to room temp, and concentrated in vacuo. The residuewas dissolved in EtOAc and washed with H₂O, saturated NaHCO₃ and brinethen dried over Na₂SO₄ and concentrated in vacuo. Purification bychromatography (50-60% EtOAc-hexanes) gave1-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methoxy-2-(4-morpholinophenyl)ethanolas a colorless residue (0.234, 79% yield).

To a solution of1-(5-(4-bromo-3,5-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2-methoxy-2-(4-morpholinophenyl)ethanol(0.18 g, 0.35 mmol) in anhydr CH₂Cl₂ (4 mL) under argon was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.198 g,0.47 mmol). After stirring at room temperature for 50 min, the mixturewas diluted with Et₂O, saturated aqueous NaHCO₃ and 20% Na₂S₂O₃. Thelayers were separated and the organic layer was washed with saturatedNaHCO₃, dried over Na₂SO₄ and concentrated in vacuo. Purification bychromatography (40-50% EtOAc-hexanes) gave the product as a brightyellow solid (0.1249 g, 70% yield). MS: m/z 518.1 [M+H]⁺.

Example 551-(4-(4-Bromo-3,5-Dimethoxyphenyl)-5-Methyloxazol-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

An oven-dried flask under argon was charged with4-bromo-3,5-dimethoxybenzaldehyde (5.0 g, 20.4 mmol) and anhydrous THF(30 mL). The mixture was cooled over ice then a solution of ethylmagnesium bromide (3.0 M in diethyl ether, 8.2 mL, 24.5 mmol) was addeddropwise from an addition funnel over a period of 45 min. After stirringfor 20 min, the mixture was allowed to warm to room temperature andstirred for 19 hrs. After quenching with a solution of aqueous NH₄Cl, itwas diluted with H₂O and EtOAc then cooled over an ice bath. After themixture was cooled, the layers were separated. The organics were washedwith H₂O and brine then dried over Na₂SO₄ and concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ and concentrated in vacuo again to give1-(4-bromo-3,5-dimethoxyphenyl)propan-1-ol as a clear oil (5.43 g, 97%yield). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-ol (5.4 g, 19.6mmol) in anhydrous CH₂Cl₂ (75 mL) was added MnO₂ (17 g, 196 mmol). Afterthe mixture was placed under a drying tube and stirred at roomtemperature for 22 hrs, it was filtered through a pad of Celite andsilica gel and rinsed with EtOAc. Concentration of the filtrate in vacuogave 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one as a white solid (5.4g, 100% yield). The product was used without further purification.

To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one (1.50 g,5.49 mmol) in anhydrous THF (20 mL) was added pyridinium tribromide(1.93 g, 6.04 mmole). The reaction was stirred at room temperature for 2hrs then neutralized with a solution of saturated aqueous NaHCO₃. Themixture was extracted with EtOAc the combined organics were washed withsaturated aqueous NaHCO₃ and brine then dried over Na₂SO₄ andconcentrated in vacuo. Purification by chromatography (10-20%EtOAc-hexanes) gave 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propan-1-oneas an orange oil (1.09 g, 56% yield).

A solution of 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one (1.07g, 3.04 mmol) in formamide (10 mL) in an oven-dried flask under argonwas heated at 110° C. for 16 hrs. After cooling to room temp, EtOAc andsaturated aqueous NaHCO₃ were carefully added and the mixture wasstirred for 15 minutes. It was then extracted with EtOAc twice and thecombined organics were washed with H₂O and brine, dried over Na₂SO₄ andconcentrated. Purification by chromatography (30% EtOAc-hexanes) gave4-(4-bromo-3,5-dimethoxyphenyl)-5-methyloxazole as a yellow solid (0.496g, 55% yield).

1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-methyloxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanonewas prepared from 4-(4-bromo-3,5-dimethoxyphenyl)-5-methyloxazole andN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to theprocedure used in Example 30. Purification by chromatography (40%EtOAc-hexanes) gave the product as a yellow solid (0.048 g, 13% yield).MS: m/z 531.1 [M+H]⁺.

Example 561-(5-(4-Bromo-3,5-Dimethoxyphenyl)Oxazol-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

A solution of 4-bromo-3,5-dimethoxybenzaldehyde (5.04 g, 20.57 mmole)and toluenesulfonylmethyl isocyanide (4.22 g, 21.6 mmole) in MeOH (50ml) was heated at reflux for 3 hrs. After evaporation to near dryness,H₂O (50 ml) and EtOAc (200 ml) were added with stirring. The organiclayer was separated and washed with brine (50 ml), dried over Na₂SO₄ andconcentrated in vacuo. Et₂O (50 ml) was added with swirling and theproduct was collected by filtration, washed with Et₂O (2×25 ml) anddried giving 5-(4-bromo-3,5-dimethoxyphenyl)oxazole as a pale yellowsolid (2.25 g, 39% yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 5-(4-bromo-3,5-dimethoxyphenyl)oxazole andN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to theprocedure used in Example 30. Recrystallization from EtOAc gave theproduct as a yellow solid (0.308 g, 56% yield). MS: m/z 517.3 [M+H]⁺.

Example 571-(5-(4-Bromo-3,5-Dimethoxyphenyl)Thiophen-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

2-(4-Bromo-3,5-dimethoxyphenyl)thiophene was prepared from2-bromo-5-iodo-1,3-dimethoxybenzene and thiophen-2-ylboronic acidaccording to the procedure used in Example 12. Purification bychromatography (0-10% EtOAc-hexanes) gave a yellow solid (0.624 g, 55%yield).

1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophen-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (70% EtOAc-hexanes) gave the product as a yellow foam(0.031 g, 11% yield). MS: m/z 529.2 [M+H]⁺.

Example 581-(4-(4-Bromo-3,5-Dimethoxyphenyl)-5-(Trifluoromethyl)Oxazol-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanonewas prepared from4-(4-bromo-3,5-dimethoxyphenyl)-5-(trifluoromethyl)oxazole (preparedfrom 4-bromo-3,5-dimethoxybenzaldehyde according to Heterocycles, 1992,34, 1047) and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (20-40% EtOAc-hexanes) gave the product as a yellow solid(0.032 g, 14% yield). MS: m/z 585.3 [M+H]⁺.

Example 591-(5-(4-Bromo-3,5-Dimethoxyphenyl)Thiophen-2-Yl)-2-Methoxy-2-(4-Morpholinophenyl)Ethanone

1-(5-(4-Bromo-3,5-dimethoxyphenyl)thiophen-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanonewas prepared from 2-(4-bromo-3,5-dimethoxyphenyl)thiophene andN,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to theprocedure used in Example 30. Purification by chromatography (40%EtOAc-hexanes) gave the product as a yellow solid (0.122 g, 46% yield).MS: m/z 532.4 [M+H]⁺.

Example 602-(4-(5-Cyclopropyl-1,3,4-Oxadiazol-2-Yl)Phenyl)-2-Methoxy-1-(5-(3,4,5-Trimethoxyphenyl)Furan-2-Yl)Ethanone

2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanonewas prepared from 2-(3,4,5-trimethoxyphenyl)furan and2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc-hexanes) gave the product as a pale yellowsolid (0.129 g, 42% yield). MS: m/z 491.1 [M+H]⁺.

Example 611-(5-(4-Chloro-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc-hexanes) gave the product as a pale yellowsolid (0.116 g, 25% yield). MS: m/z 469.1 [M+H]⁺.

Example 621-(5-(4-Fluoro-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Methoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

1-(5-(4-Fluoro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas prepared from 2-(4-fluoro-3,5-dimethoxyphenyl)furan andN,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc-hexanes) gave the product as a pale yellowsolid (0.036 g, 8% yield). MS: m/z 453.2 [M+H]⁺.

Example 631-(5-(4-Chloro-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Ethoxy-2-(4-(5-Methyl-1,3,4-Oxadiazol-2-Yl)Phenyl)Ethanone

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanonewas prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamideaccording to the procedure used in Example 30. Purification bychromatography (60% EtOAc-hexanes) gave the product as a pale yellowsolid (0.122 g, 25% yield). MS: m/z 483.1 [M+H]⁺.

Example 641-(5-(4-Chloro-3,5-Dimethoxyphenyl)Furan-2-Yl)-2-Ethoxy-2-(4-Morpholinophenyl)Ethanone

1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-morpholinophenyl)ethanonewas prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and2-ethoxy-N-methoxy-N-methyl-2-(4-morpholinophenyl)acetamide according tothe procedure used in Example 30. Purification by chromatography (60%EtOAc-hexanes) gave the product as a pale yellow solid (0.127 g, 26%yield). MS: m/z 486.5 [M+H]⁺.

Example 65 Synthesis of Further Representative Compounds

The following representative compounds in Table 1 were synthesizedaccording to (i) the foregoing procedures by selecting appropriatestarting materials and (ii) known organic synthesis techniques.

TABLE 1 Compound MS m/z No. Structure [M + H]⁺ 65-1

517.3 65-2

499.3 65-3

514.0 [M − H]⁻ 65-4

499.3 65-5

499.3 65-6

512.4 65-7

468.2 65-8

481.1 65-9

449.2 65-10

499.1 65-11

543   65-12

460.2 65-13

467.4 65-14

469.1 65-15

451.2 65-16

459.1 65-16

541.0 65-17

482.2

The following representative compounds in Table 2 are synthesizedaccording to (i) the foregoing procedures by selecting appropriatestarting materials and (ii) known organic synthesis techniques.

TABLE 2 Compound No. Structure MW 65-18

453.49 65-19

496.95 65-20

460.49 65-21

527.38 65-22

482.53 65-23

469.51 65-24

464.47 65-25

480.54 65-26

467.52

Example 66 Compound Assay PDE10 Biochemical Assay

The phosphodiesterase (PDE) assay was performed using recombinant humanPDE 1A3, 2A3, 3 catalytic region, 4 catalytic region, 5 catalyticregion, 7A, 8A, 9A2, 10A1 and 11A1 enzymes expressed in a baculoviralsystem using Sf9 cells. PDE activity was measured using a modificationof the two-step method of Thompson and Appleman described above whichwas adapted for 96 well plate format. The effect of the PDE inhibitorswas determined by assaying a fixed amount of the enzyme in the presenceof test compound concentrations and a substrate concentration below thatof the Km, so that Ki equals IC₅₀. The final assay volume was 110 μlwith assay buffer (10 mM MgCl₂; 40 mM Tris.HCl; pH 7.4). Reactions wereinitiated with enzyme and incubated with (³H)-substrate and substancefor 20 minutes at 30° C. The reaction was terminated by denaturing theenzyme (heating the reaction to 70° C. for 2 minutes). The reaction wasthen cooled at 4° C. for 10 minutes before the addition of snake venom(Crotalus atrox, 0.2 mg/ml) for 10 minutes at 30° C., thus allowingnon-specific hydrolysis of the tritiated substrate. Separation of theremaining unhydrolysed cyclic nucleotide was achieved by a batch bindingof the mixture to activated Dowex (200 μl) anion exchange resin. Theanion exchange resin bound the charged nucleotides, leaving onlyhydrolysed (³H) substrate in the soluble fraction. The soluble fraction(50 μl) was then added to microscint-20 (200 μl) and counted on a TopCount Plate reader. Radioactivity units were plotted against inhibitorconcentration and IC₅₀ values obtained using Graph Pad Prism software.

Alternatively, phosphodiesterase activity was measured by scintillationproximity assay (SPA) with [³H]-cGMP as substrate. Purified PDE10 wasdiluted and stored in 25 mM Tris-Cl (pH 8.0)/100 mM NaCl/0.05% Tween20/50% glycerol/3 mM DTT. Assays contained (final concentrations): 50 mMTris-Cl (pH 7.5)/8.3 mM MgCl₂/1.7 mM EGTA/0.5 mg/ml BSA/5% DMSO and 2 ngPDE10 in a final volume of 0.1 mL. Inhibition was evaluated at 8concentrations in duplicate. Reactions were initiated by addition ofenzyme and were terminated after 20 minutes at 30° C. by the addition of50 μl of SPA beads containing Zn⁺⁺. The mixture was shaken, allowed tosettle for 3 hours, and counted in a Wallac plate counter. Results (netcpm) were fitted to a four parameter logistic model using Excel Solver®.

Further, the inhibition of other PDE enzymes by the PDE10 inhibitors wasevaluated under the same conditions described above for PDE10 except theamount of enzyme added was optimized for each PDE. Fractional inhibitionwas evaluated at four concentrations (0.1, 1, 10, and 100 μM). In caseswhere inhibition at the highest concentration was less than 50%, thelower limit value in the logistic model was fixed to 0% activity.

In the above assay, compounds of this invention are PDE10 inhibitorswith an IC₅₀ of 100 μM or less, generally less than 10 μM, and typicallyless than 1 μM. To this end, compounds 1-1, 2-1, 3-1, 4-1, 5-1, 6-1,7-1, 8-1, 9-1, 10-1, 11-1, 12-1, 13-1, 14-1, 15-1, 16-1, 17-1, 18-1,19-1, 20-1, 21-1, 22-1, 23-1, 25-1, 26-1, 27-1, 28-1, 29-1, 30-1, 31-1,32-1, 33-1, 34-1, 35-1, 36-1, 37-1, 38-1, 39-1, 40-1, 41-1, 42-1, 43-1,44-1, 45-1, 46-1, 47-1, 48-1, 49-1, 50-1, 51-1, 52-1, 53-1, 54-1, 55-1,56-1, 57-1, 58-1, 59-1, 60-1, 61-1, 62-1, 63-1, 64-1, 65-1, 65-2, 65-3,65-4, 65-5, 65-6, 65-7, 65-8, 65-9, 65-10, 65-11, 65-12, 65-13, 65-14,and 65-15 for example, were found to have IC₅₀ values of less than orequal to 1 μM.

Examples 67-77 Evaluation of Representative Compounds in BehavioralModels

Schizophrenia has been associated with dysfunctions of dopaminergic,glutamatergic and serotonergic neurotransmission. Psychostimulant drugsin these three classes, dopaminergic agonists (such as amphetamine andapomorphine), glutamatergic antagonists (such as phencyclidine (PCP) andketamine), and serotonergic agonists (such as LSD and MDMA), all inducepsychotomimetic states (e.g., hyperactivity and disruption of prepulseinhibition) in animals, that closely resemble schizophrenia symptoms inhumans. Known antipsychotic drugs, including both typical antipsychotics(e.g., haloperidol) and atypical antipsychotics (e.g., olanzapine),reverse such psychotomimetic states in animals. Examples 67-77 describedbelow evaluate representative compounds of the present invention inanimal behavioral models to allow comparison of the resulting effect tothat of known antipsychotics. Methods used in the Examples 67-77 are asfollows.

Dosing of the compounds is by intraperitoneal (i.p.) injection or oralgavage (p.o.). Intraperitoneal injection is accomplished by restrainingthe animal, exposing the abdomen and inserting the needle just above theknees on the mouse's right side. Oral gavage is performed by restrainingthe animal in such a way that its head is tilted back and the esophagusis relatively straight. The gavage needle (20 G×1.5″, Cadence Science)is inserted into the mouth in line with the body and gently pushed alongthe esophagus and into the stomach. If resistance is encountered theneedle is removed and reinserted.

Psychostimulant-induced hyperactivity is measured by injecting animalswith PCP and monitoring the animals' activity levels in VersaMaxchambers (Accuscan Instruments, Columbus, Ohio) measuring 40×40 cm.Locomotor activity is detected by photobeam breaks as the animal crosseseach beam. The animal is placed in the center of the field and leftundisturbed for 20 minutes to measure its spontaneous activity in anovel environment. Measurements used to assess locomotor activityinclude: horizontal activity, total distance traveled, vertical activity(rearing events—animal raises up on hindlimbs), rotation, stereotypy,and distance traveled in the center compared to total distance traveled(center: total distance ratio). The NMDA antagonist PCP induces apsychosis-like syndrome manifest as hyperactivity and increasedstereotypic behavior. Known antipsychotics are able to reversepsychostimulant-induced hyperactivity and stereotypy.

Conditioned avoidance response (CAR) is a behavioral test to evaluatethe antipsychotic effect of a test compound. It utilizes a shuttle box(Med Associates, St. Albans, Vt.) with two identical chambers separatedby a retractable door. Each chamber is fitted with a metal grid floorthat is capable of delivering electric shocks independently. A computerprogram is used to implement the testing paradigm as well as record theanimal's movement between the two chambers through infrared beamsensors. The testing paradigm is as follows. A mouse is placed into onechamber. A light (conditioned stimulus, CS) comes on. Five secondslater, mild electric shocks (0.4 mA; (unconditioned stimulus, US) aredelivered to the chamber where the mouse is located (as detected byinfrared beams) until the mouse escapes to the adjacent chamber or until10 sec has elapsed. The US and CS always co-terminate. With randomizedinter-trial intervals averaging 15 sec, 30 such CS-US pairing trials aregiven to each mouse each day. For each trial, an escape response isregistered if the mouse crosses to the other chamber after being shocked(i.e., during the 10-sec US period), and an avoidance response isregistered if the mouse crosses to the other chamber during the first5-sec CS only period. The animals are trained in this paradigm for 30-40days, during which the average percentage of avoidance responses willimprove to 80-90%. This indicates that animals have learned to avoid theonset of footshocks by moving to the opposite chamber upon activation ofthe CS (light). These trained animals are then used for compound testingwith the same paradigm. Known antipsychotics have been found to inhibitthe conditioned avoidance response, and the ability of new compounds toinhibit this response is thought to be predictive of antipsychoticeffects in humans.

Example 67 Reduction of PCP-Induced Hyperactivity by Compound 1-1

Compound 1-1 (Example 1) was found to reduce PCP-induced hyperactivity,as shown in FIGS. 1 and 2. C57BL/6 male mice were given either compound1-1 or vehicle by intraperitoneal injection (FIG. 1) or oral gavage(FIG. 2). Twenty minutes (for i.p.) or forty minutes (for p.o.) later,they were injected with PCP (5 mg/kg, i.p.). Ten minutes later, the micewere placed in activity chambers and their locomotor activity in thehorizontal dimension was monitored by infrared beam breaks for 20 min (5consecutive 4-minute intervals (INT) as indicated). FIG. 1 shows thatcompound 1-1 (10 mg/kg) significantly reduces the hyperactivity inducedby PCP, as seen by comparison to the vehicle+PCP control (p=0.0088, n=8per group, independent sample t-test). FIG. 2 shows that compound 1-1 isalso effective when given by oral gavage (p=0.0045, n=8 per group,independent sample t-test)

Example 68 Reduction of PCP-Induced Hyperactivity by Compound 2-1

Compound 2-1 (Example 2) was found to reduce PCP-induced hyperactivity,as shown in FIGS. 3 and 4. C57BL/6 male mice were given either compound2-1 or vehicle by intraperitoneal injection (FIG. 3) or oral gavage(FIG. 4). Twenty minutes (for i.p.) or 40 minutes (for p.o.) later, theywere injected with PCP (5 mg/kg, i.p.). Ten minutes later, the mice wereplaced in activity chambers and their locomotor activity in thehorizontal dimension was monitored by infrared beam breaks for 20 min (5consecutive 4-minute intervals (INT) as indicated). FIG. 3 shows thatcompound 2-1 (10 mg/kg) significantly reduces the hyperactivity inducedby PCP, as seen by comparison to the vehicle+PCP control (p=0.0021, n=8per group, independent sample t-test). FIG. 4 shows that compound 2-1 isalso effective when given by oral gavage (p=0.000005 for 10 mg/kg dose,n=8 per group, independent sample t-test)

Example 69 Reduction of Conditioned Avoidance Response by Compound 2-1

Compound 2-1 (Example 2) was found to reduce Conditioned AvoidanceResponses (CAR), as shown in FIG. 5. C57BL/6 male mice were trained inthe CAR paradigm to predict and avoid the noxious stimulus (foot shock),reaching a plateau of approximately 25 avoidance responses per 30 trialseach day. The mice were then given either vehicle or compound 2-1 viaoral gavage, 30 minutes before testing for 30 trials in the CARparadigm. Vehicle treatment and compound treatment were given to thesame animals on alternating days, and the effect of compound in reducingavoidance response was analyzed through within-subject comparison(paired t-test). Vehicle exposure does not alter the avoidance responseof these trained animals. FIG. 5 shows that compound 2-1 (12 mg/kg)significantly reduces the number of avoidance response (p=0.0048, n=7per group, paired t-test).

Example 70 Reduction of PCP-Induced Hyperactivity by Compound 11-1

Compound 11-1 (Example 11) was found to reduce PCP-inducedhyperactivity, as shown in FIG. 6. C57BL/6 male mice were given eithercompound 11-1 or vehicle by intraperitoneal injection. Five minuteslater they were injected with PCP (5 mg/kg, i.p.). Ten minutes later,the mice were placed in activity chambers and their locomotor activityin the horizontal dimension was monitored by infrared beam breaks for 20min (5 consecutive 4-minute intervals (INT) as indicated). FIG. 6 showsthat compound 11-1 (10 mg/kg) significantly reduces the hyperactivityinduced by PCP, as seen by comparison to the vehicle+PCP control(p=0.00040, n=8 per group, independent sample t-test).

Example 71 Reduction of Conditioned Avoidance Response by Compound 34-1

Compound 34-1 (Example 34) was found to reduce Conditioned AvoidanceResponses (CAR), as shown in FIG. 7. C57BL/6 male mice were trained inthe CAR paradigm to predict and avoid the noxious stimulus (foot shock),reaching a plateau of approximately 25-28 avoidance responses per 30trials (“training plateau”) each day. The mice were then given eithervehicle or compound (25 minutes prior to testing) via oral gavage, andthen were tested for 30 trials in the CAR paradigm. Vehicle treatmentand compound treatment were given to the same animals on alternatingdays, and the effect of compound in reducing avoidance response wasanalyzed through within-subject comparison (paired t-test). Vehicleexposure (“vehicle”) does not alter the avoidance response of thesetrained animals. FIG. 7 shows that compound 34-1 significantly reducesthe number of avoidance responses at 10 mg/kg (p=0.0003, n=7 per group).

Example 72 Reduction of Conditioned Avoidance Response by Compound 36-1

Compound 36-1 (Example 36) was found to reduce Conditioned AvoidanceResponses (CAR), as shown in FIG. 8. C57BL/6 male mice were trained inthe CAR paradigm to predict and avoid the noxious stimulus (foot shock),reaching a plateau of approximately 25-28 avoidance responses per 30trials (“training plateau”) each day. The mice were then given eithervehicle or compound (25 minutes prior to testing) via oral gavage, andthen were tested for 30 trials in the CAR paradigm. Vehicle treatmentand compound treatment were given to the same animals on alternatingdays, and the effect of compound in reducing avoidance response wasanalyzed through within-subject comparison (paired t-test). Vehicleexposure (“vehicle”) does not alter the avoidance response of thesetrained animals. FIG. 8 shows that compound 36-1 significantly reducesthe number of avoidance responses at 15 mg/kg (p=0.000014, n=5 pergroup) and shows a trend that did not reach significance at 5 and 10mg/kg.

Example 73 Reduction of Conditioned Avoidance Response by Compound 47-1

Compound 47-1 (Example 47) was found to reduce Conditioned AvoidanceResponses (CAR), as shown in FIG. 9. C57BL/6 male mice were trained inthe CAR paradigm to predict and avoid the noxious stimulus (foot shock),reaching a plateau of approximately 25-28 avoidance responses per 30trials (“training plateau”) each day. The mice were then given eithervehicle or compound (55 minutes prior to testing) via oral gavage, andthen were tested for 30 trials in the CAR paradigm. Vehicle treatmentand compound treatment were given to the same animals on alternatingdays, and the effect of compound in reducing avoidance response wasanalyzed through within-subject comparison (paired t-test). Vehicleexposure (“vehicle”) does not alter the avoidance response of thesetrained animals. FIG. 9 shows that compound 47-1 significantly reducesthe number of avoidance responses at 5 and 10 mg/kg (p=0.0002 and p=3.3E-10, respectively, n=8 per group) and shows a trend that did not reachsignificance at 2 mg/kg.

Example 74 Reduction of Conditioned Avoidance Response by Compound 61-1

Compound 61-1 (Example 61) was found to reduce Conditioned AvoidanceResponses (CAR), as shown in FIG. 10. C57BL/6 male mice were trained inthe CAR paradigm to predict and avoid the noxious stimulus (foot shock),reaching a plateau of approximately 25-28 avoidance responses per 30trials (“training plateau”) each day. The mice were then given eithervehicle or compound (55 minutes prior to testing) via oral gavage, andthen were tested for 30 trials in the CAR paradigm. Vehicle treatmentand compound treatment were given to the same animals on alternatingdays, and the effect of compound in reducing avoidance response wasanalyzed through within-subject comparison (paired t-test). Vehicleexposure (“vehicle”) does not alter the avoidance response of thesetrained animals. FIG. 10 shows that compound 61-1 significantly reducesthe number of avoidance responses at 2, 5, and 10 mg/kg (p=0.015,p=0.00008 and p=2.1 E-7, respectively, n=5 per group).

Example 75 Reduction of Conditioned Avoidance Response by Compound 63-1

Compound 63-1 (Example 63) was found to reduce Conditioned AvoidanceResponses (CAR), as shown in FIG. 11. C57BL/6 male mice were trained inthe CAR paradigm to predict and avoid the noxious stimulus (foot shock),reaching a plateau of approximately 25-28 avoidance responses per 30trials (“training plateau”) each day. The mice were then given eithervehicle or compound (55 minutes prior to testing) via oral gavage, andthen were tested for 30 trials in the CAR paradigm. Vehicle treatmentand compound treatment were given to the same animals on alternatingdays, and the effect of compound in reducing avoidance response wasanalyzed through within-subject comparison (paired t-test). Vehicleexposure (“vehicle”) does not alter the avoidance response of thesetrained animals. FIG. 11 shows that compound 63-1 significantly reducesthe number of avoidance responses at 2, 5, and 10 mg/kg (p=0.0099,p=0.00011, and p=6.6 E-16 respectively, n=6 per group).

Example 76 Reduction of Conditioned Avoidance Response by Compound 49-1

Compound 49-1 (Example 49) was found to reduce Conditioned AvoidanceResponses (CAR), as shown in FIG. 12. C57BL/6 male mice were trained inthe CAR paradigm to predict and avoid the noxious stimulus (foot shock),reaching a plateau of approximately 25-28 avoidance responses per 30trials (“training plateau”) each day. The mice were then given eithervehicle or compound (55 minutes prior to testing) via oral gavage, andthen were tested for 30 trials in the CAR paradigm. Vehicle treatmentand compound treatment were given to the same animals on alternatingdays, and the effect of compound in reducing avoidance response wasanalyzed through within-subject comparison (paired t-test). Vehicleexposure (“vehicle”) does not alter the avoidance response of thesetrained animals. FIG. 12 shows that compound 49-1 significantly reducesthe number of avoidance responses at 10 mg/kg (p=5.7 E-9, n=8 pergroup).

Example 77 Reduction of Conditioned Avoidance Response by Compound 65-10

Compound 65-10 (Example 65, Table 1) was found to reduce ConditionedAvoidance Responses (CAR), as shown in FIG. 13. C57BL/6 male mice weretrained in the CAR paradigm to predict and avoid the noxious stimulus(foot shock), reaching a plateau of approximately 25-28 avoidanceresponses per 30 trials (“training plateau”) each day. The mice werethen given either vehicle or compound (55 minutes prior to testing) viaoral gavage, and then were tested for 30 trials in the CAR paradigm.Vehicle treatment and compound treatment were given to the same animalson alternating days, and the effect of compound in reducing avoidanceresponse was analyzed through within-subject comparison (paired t-test).Vehicle exposure (“vehicle”) does not alter the avoidance response ofthese trained animals. FIG. 13 shows that compound 65-10 significantlyreduces the number of avoidance responses at 5 and 10 mg/kg (p=0.0145and p=0.00011; n=8 per group).

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

1-47. (canceled)
 48. A compound having the following structure (I-E):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopethereof, wherein: R₁ is C₁₋₆alkyl; R₂ is aryl substituted withC₁₋₆alkoxy or substituted or unsubstituted heterocyclyl; and R₃ is arylsubstituted with at least one halogen, alkyl, hydroxy, alkoxy, or cyano.49. The compound of claim 48, wherein R₁ is methyl, ethyl, or propyl.50. The compound of claim 48, wherein R₂ is phenyl substituted withC₁₋₆alkoxy or substituted or unsubstituted heterocyclyl.
 51. Thecompound of claim 50, wherein R₂ is phenyl substituted withunsubstituted heterocyclyl.
 52. The compound of claim 51, wherein R₂ isphenyl substituted with morpholino, pyrazolyl, triazolyl, pyridinyl, orpyrazinyl.
 53. The compound of claim 50, wherein R₂ is phenylsubstituted with substituted heterocyclyl.
 54. The compound of claim 53wherein the substituted heterocyclyl is substituted with a halogensubstituent.
 55. The compound of claim 53, wherein the substitutedheterocyclyl is substituted with a C₁₋₆alkyl substituent.
 56. Thecompound of claim 55, wherein the C₁₋₆alkyl substituent is methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.57. The compound of claim 55, wherein the substituted heterocyclyl isthiadiazolyl, oxadiazolyl, thiazolyl, or furanyl substituted with aC₁₋₆alkyl substituent.
 58. The compound of claim 48, wherein R₃ isphenyl substituted with at least one halogen, alkyl, hydroxy, alkoxy, orcyano.
 59. The compound of claim 58, wherein R₃ is phenyl substitutedwith at least one halogen and at least one alkoxy.
 60. The compound ofclaim 58, wherein R₃ is 4-bromo-3,5-dimethoxyphenyl,4-chloro-3,5-dimethoxyphenyl, 4-fluoro-3,5-dimethoxyphenyl,3-bromo-4,5-dimethoxyphenyl, 3-chloro-4,5-dimethoxyphenyl,3-fluoro-4,5-dimethoxyphenyl, 4-cyano-3,5-dimethoxyphenyl,3-cyano-4,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,4-hydroxy-3,5-dimethoxyphenyl, or 4-methyl-3,5-dimethoxyphenyl.
 61. Thecompound of claim 48, wherein R₁ is methyl, ethyl, or propyl; R₂ isphenyl substituted with substituted heterocyclyl; and R₃ is phenylsubstituted with at least one halogen and at least one alkoxy.
 62. Thecompound of claim 61, wherein the substituted heterocyclyl of R₂ issubstituted with a C₁₋₆alkyl substituent.
 63. The compound of claim 62,wherein the substituted heterocyclyl of R₂ is thiadiazolyl.
 64. Thecompound of claim 63, wherein the substituted thiadiazolyl of R₂ issubstituted with methyl, ethyl, isopropyl, or tert-butyl.
 65. Thecompound of claim 64, wherein R₃ is phenyl substituted with at least onechloro or bromo and at least one methoxy.
 66. The compound of claim 48,wherein the compound is:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopethereof.
 67. The compound of claim 48, wherein the compound is anisotope having one or more atoms replaced by the same atom having adifferent atomic mass.
 68. The isotope of claim 67, wherein one or moreH atoms is replaced by ²H.
 69. The isotope of claim 67, wherein one ormore H atoms is replaced by ³H.
 70. The isotope of claim 67, wherein oneor more C atoms is replaced by ¹⁴C.
 71. An isotope of a compound havingthe following structure:

or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof,wherein one or more atoms of the compound are replaced by the same atomhaving a different atomic mass.
 72. The isotope of claim 71, wherein oneor more H atoms is replaced by ²H.
 73. The isotope of claim 71, whereinone or more H atoms is replaced by ³H.
 74. The isotope of claim 71,wherein one or more C atoms is replaced by ¹⁴C.
 75. The isotope of claim71, wherein one or more H atoms of a compound having the followingstructure is replaced by ²H:


76. The isotope of claim 71, wherein one or more H atoms of a compoundhaving the following structure is replaced by ³H:


77. A pharmaceutical composition comprising a compound of any one ofclaims 48, 67, and 71 to 76 and a pharmaceutically acceptable carrier ordiluent.
 78. A method for inhibiting PDE10 in a warm-blooded animal,comprising administering to the animal an effective amount of apharmaceutical composition of claim
 77. 79. A method for treatingneurological disorders in a warm-blooded animal in need thereof,comprising administering to the animal an effective amount of apharmaceutical composition of claim
 77. 80. The method of claim 79wherein the neurological disorder is selected from the group consistingof psychotic disorders, anxiety disorders, movement disorders and/orneurological disorders such as Parkinson's disease, Huntington'sdisease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia,Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette'ssyndrome, schizophrenia, delusional disorders, bipolar disorders,post-traumatic stress disorders, drug-induced psychosis, panicdisorders, obsessive-compulsive disorders, attention-deficit disorders,disruptive behavior disorders, autism, depression, dementia, cognitivedisorders, epilepsy, insomnias and multiple sclerosis.
 81. The method ofclaim 80 wherein the neurological disorder is Huntington's disease. 82.The method of claim 80 wherein the neurological disorder isschizophrenia.